MuO-conopeptides and their use as local anesthetics

ABSTRACT

The present invention is directed to the new μO-conopeptides, their coding sequences and their propeptides and to the use of μO-conopeptides as a local anesthetic for treating pain. The μO-conopeptides have long lasting anesthetic activity and are particularly useful for spinal anesthesia, either administered acutely for post-operative pain or via an intrathecal pump for severe chronic pain situations or for treatment of pain in epithelial tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application is a continuation-in-part of Ser. No.09/590,386 filed on Jun. 9, 2000 and claims benefit thereto. The presentapplication also claims benefit under 35 USC §119(e) to U.S. provisionalpatent applications Ser. No. 60/138,507 filed on Jun. 10, 1999 and Ser.No. 60/219,451 filed on Jul. 20, 2000. Each of these applications isincorporated herein by reference.

[0002] This invention was made with Government support under Grant No.GM48677 awarded by the National Institute of General Medical Sciences,National Institutes of Health, Bethesda, Md. The United StatesGovernment has certain rights in the invention.

BACKGROUND OF THE INVENTION

[0003] The present invention is directed to the use of μO-conopeptidesas a local anesthetic for treating pain. The μO-conopeptides havelong-lasting anesthetic activity and are particularly useful for spinalanesthesia, administered either acutely for post-operative pain or viaan intrathecal pump for severe chronic pain situations. The presentinvention is further directed to new μO-conopeptides, their codingsequences and their propeptides.

[0004] The publications and other materials used herein to illuminatethe background of the invention, and in particular, cases to provideadditional details respecting the practice, are incorporated herein byreference, and for convenience, are referenced by author and date in thefollowing text and respectively grouped in the appended Bibliography.

[0005] Conus is a genus of predatory marine gastropods (snails) whichenvenomate their prey. Venomous cone snails use a highly developedprojectile apparatus to deliver their cocktail of toxic conotoxins intotheir prey. In fish-eating species such as Conus magus the cone detectsthe presence of the fish using chemosensors in its siphon and when closeenough extends its proboscis and fires a hollow harpoon-like toothcontaining venom into the fish. This immobilizes the fish and enablesthe cone snail to wind it into its mouth via an attached filament. Forgeneral information on Conus and their venom see the website addresshttp://grimwade.biochem.unimelb.edu.au/cone/referenc.html. Prey captureis accomplished through a sophisticated arsenal of peptides which targetspecific ion channel and receptor subtypes. Each Conus species venomappears to contain a unique set of 50-200 peptides. The composition ofthe venom differs greatly between species and between individual snailswithin each species, each optimally evolved to paralyse it's prey. Theactive components of the venom are small peptides toxins, typically12-30 amino acid residues in length and are typically highly constrainedpeptides due to their high density of disulphide bonds.

[0006] The venoms consist of a large number of different peptidecomponents that when separated exhibit a range of biological activities:when injected into mice they elicit a range of physiological responsesfrom shaking to depression. The paralytic components of the venom thathave been the focus of recent investigation are the α-, ω- andμ-conotoxins. All of these conotoxins act by preventing neuronalcommunication, but each targets a different aspect of the process toachieve this. The α-conotoxins target nicotinic ligand gated channels,the μ-conotoxins target the voltage-gated sodium channels and theω-conotoxins target the voltage-gated calcium channels (Olivera et al.,1985). For example a linkage has been established between α-, αA- &φ-conotoxins and the nicotinic ligand-gated ion channel; ω-conotoxinsand the voltage-gated calcium channel; μ-conotoxins and thevoltage-gated sodium channel; δ-conotoxins and the voltage-gated sodiumchannel; κ-conotoxins and the voltage-gated potassium channel;conantokins and the ligand-gated glutamate (NMDA) channel. For a partiallist of Conus peptides and their amino acid sequences see the websiteaddress http://pir.georgetown.edu.

[0007] However, the structure and function of only a small minority ofthese peptides have been determined to date. For peptides where functionhas been determined, three classes of targets have been elucidated:voltage-gated ion channels; ligand-gated ion channels, andG-protein-linked receptors.

[0008] Conus peptides which target voltage-gated ion channels includethose that delay the inactivation of sodium channels, as well asblockers specific for sodium channels, calcium channels and potassiumchannels. Peptides that target ligand-gated ion channels includeantagonists of NMDA and serotonin receptors, as well as competitive andnoncompetitive nicotinic receptor antagonists. Peptides which act onG-protein receptors include neurotensin and vasopressin receptoragonists. The unprecedented pharmaceutical selectivity of conotoxins isat least in part defined by a specific disulfide bond frameworkscombined with hypervariable amino acids within disulfide loops (for areview see McIntosh et al., 1998).

[0009] The pain response is a protective reflex system warning anindividual of hostile situations and tissue injury. The origins ofclinically significant acute and chronic pain in a mammal are different,but the biochemical and neurological pathways are similar. In thefollowing discussion on pain and its management, the focus is primarilyon humans, however, it should be understood that the concepts of painare applicable to mammalian animals and the management of such pain isapplicable to veterinary medicine.

[0010] Acute pain is often associated with surgery and with trauma. Theintensity of acute postoperative pain varies considerably depending onthe extent of the surgical procedure performed, on the individual's painsensitivity, and on the type of anesthetic management employed duringsurgery. In general, major operations on the thorax and the upperabdominal region induce the most intensive postoperative pain. Extensiveorthopedic operations also produce strong postoperative pain.

[0011] Chronic pain is persistent pain which has long outlasted theonset of any known or suspected physical cause. It can occur after aknown injury or disease, or it can occur without any known physicalcause whatsoever. Moreover, it can be accompanied by known tissuepathology, such as chronic inflammation that occurs in some types ofarthritis, or it can occur long after the healing of the injured tissuewhich is suspected or known to be the cause of chronic pain. Chronicpain is a very general concept and there are several varieties ofchronic pain related to the musculoskeletal system, visceral organs,skin, and nervous system.

[0012] Neuropathic pain can occur as a form of chronic pain and can alsooccur under acute conditions such as those following surgery oraccidental trauma. Neuropathic pain can be defined as pain that resultsfrom an abnormal functioning of the peripheral and/or central nervoussystem. A critical component of this abnormal functioning is anexaggerated response of pain-related nerve cells either in theperipheral or in the central nervous system. This exaggeratedresponsiveness is manifested behaviorally as increased sensitivity topain, i.e., as hyperalgesia or allodynia, both of which can occur inchronic neuropathic and acute inflammatory pains. An example is the painfrom causalgia wherein even a light touch to the skin is felt as anexcruciating burning pain (allodynia) or a normally mild pain isexperienced as an excruciating one (hyperalgesia). Neuropathic pain isthought to be a consequence of damage to peripheral nerves or to regionsof the central nervous system. However, abnormal functioning ofpain-related regions of the nervous system call also occur with chronicinflammatory conditions such as certain types of arthritis and metabolicdisorders such as diabetes as well as with acute inflammatoryconditions. Thus, many types of chronic pains that are related toinflammation as well as acute pains that are related to inflammation canbe considered to be at least partly neuropathic pains.

[0013] The modem concept of pain treatment emphasizes the significanceof prophylactic prevention of pain, as pain is more easily preventedthan relieved. Additionally, the hormonal stress responses associatedwith pain are considered harmful to the patient, impair the healingprocess and overall recovery, and generally are to be avoided.

[0014] While compounds utilized as general anesthetics reduce pain byproducing a loss of consciousness, local anesthetics act to induce aloss of sensation in the localized area of administration in the body.The mechanism by which local anesthetics induce their effect, while nothaving been determined definitively, is generally thought to be basedupon the ability to interfere with the initiation and transmission ofthe nerve impulse conduction along an axon through a reversible blockadeof sodium channels. Currently used local anesthetics have durations ofaction lasting only several hours. While this length of duration meetsmany needs, particularly the control of acute pain, local anestheticagents with longer duration of action would have broad clinicalapplication for the treatment of postoperative and chronic pain (Kuzmaet al., 1997).

[0015] The duration of action of a local anesthetics is proportional tothe time during which it is in actual contact with the nervous tissues.In an effort to increase the duration of action, procedures orformulations that maintain localization of the drug at the nerve greatlyprolong anesthesia. All local anesthetics are potentially toxic, andtherefore it is of great importance that the choice of drug,concentration, rate and site of administration, as well as other actors,be considered in their use. On the other hand, a local anesthetic mustremain at the site long enough to allow sufficient time for thelocalized pain to subside. Different devices and formulations are knownin the art for administration of local anesthetics. See U.S. Pat. No.5,747,060, which discloses such devices and formulations.

[0016] Side effects which have been associated with the use of differentdrugs for treating pain or as local anesthetics includes includerespiratory depression, reduced cough reflex, bronchial spasms, nausea,vomiting, release of histamine, peripheral vasodilation, orthostatichypotension, vagal impact on the heart, contraction of smooth muscles(sphincters), reduced peristaltic motility in the gastrointestinaltract, urinary retention, stimulated release of adrenalin, anti-diuretichormone, changes in the regulation of body temperature and sleeppattern, tolerance, addiction, tachycardia, increase in blood pressure,and agitation. Not all of these side effects are seen with any givendrug used to treat pain.

[0017] Thus, there is a need to develop additional drugs and methodswhich can be used for the treatment of pain, which can act as localanesthetics, which have a longer duration of action and which havereduced side effects. Accordingly, an object of the invention is toprovide methods and compositions for the treatment of acute or chronicpain which provide effective control of pain with longer duration ofaction and reduced side effects associated with traditional analgesics.

SUMMARY OF THE INVENTION

[0018] The present invention is directed to the new μO-conopeptides,their coding sequences and their propeptides and to the use ofμO-conopeptides as a local anesthetic for treating pain. TheμO-conopeptides have long lasting anesthetic activity and areparticularly useful for spinal anesthesia, either administered acutelyfor post-operative pain or via an intrathecal pump for severe chronicpain situations or for treatment of pain in epithelial tissue.

[0019] More specifically, the present invention is directed toμO-conopeptides having the general formula I:

Xaa₁-Xaa₂-Cys-Xaa₃-Xaa₄-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Cys-Xaa₉-Xaa₁₀-Xaa₁₁-Xaa₁₂-Xaa₁₃-Xaa₁₄-Xaa₁₅-Xaa₁₆-Xaa₁₇-Cys-Cys-Xaa₁₈-Xaa₁₉-Xaa₂₀-Xaa₂₁-Cys-Xaa₂₂-Xaa₂₃-Xaa₂₄-Xaa₂₅-CYS-Xaa₂₆-Xaa₂₇-Xaa₂₈-Xaa₂₉-Xaa₃₀(SEQ ID NO:1),

[0020] wherein Xaa₁ is des-Xaa₁, Pro, hydroxy-Pro (Hyp), Arg, Lys,ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any synthetic basic aminoacid; Xaa₂ is des-Xaa₂, Ala, Gly, Asp, Glu, γ-carboxy-glutamate (Gla),any synthetic acidic amino acid, Thr, Ser, g-Thr (where g isglycosylation), g-Ser, Trp (D or L), neo-Trp or halo-Trp (D or L) orXaa₂ may be pyroglutamate if Xaa₁ is des-Xaa₁; Xaa₃ is Arg, Lys,ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any synthetic basic aminoacid, Ser, Thr, g-Ser, g-Thr, Ala, an aliphatic amino acid bearinglinear or branched saturated hydrocarbon chains such as Leu (D or L),Ile and Val or non-natural derivatives of the aliphatic amino acid, His,Glu, Gln, Gla, Asp, Asn or any synthetic acidic amino acid; Xaa₄ is Glu,Gla, Gln, Asp, Asn, any synthetic acidic amino acid, Lys, Arg,ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any synthetic basic aminoacid, Ala, an aliphatic amino acid bearing linear or branched saturatedhydrocarbon chains such as Leu (D or L), Ile and Val or non-naturalderivatives of the aliphatic amino acid, Ser, Thr, Pro, Hyp, g-Ser,g-Thr, g-Hyp or any synthetic hydroxylated amino acid; Xaa₅ is Lys, Arg,ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any synthetic basic aminoacid, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, an aliphatic amino acid bearinglinear or branched saturated hydrocarbon chains such as Leu (D or L),Ile and Val or non-natural derivatives of the aliphatic amino acid, Glu,Gla, Gln, Asp, Asn, any synthetic acidic amino acid, Pro or Hyp; Xaa₆ isTrp (D or L), neo-Trp, halo-Trp (D or L), Gly, Tyr, meta-Tyr, ortho-Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr, Glu, Gla, Gln, Asp, Asn, any synthetic acidic amino acid;Xaa₇ is Glu, Gla, Gin, Asp, Asn, any synthetic acidic amino acid, Met,norleucine (Nle), Ala, an aliphatic amino acid bearing linear orbranched saturated hydrocarbon chains such as Leu (D or L), Ile and Valor non-natural derivatives of the aliphatic amino acid, Tyr, meta-Tyr,ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr, Lys, Arg, ornithine, homo-Lys, homoarginine,nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or anysynthetic basic amino acid; Xaa₈ is Leu, Phe, Tyr, meta-Tyr, ortho-Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr, Trp (D or L), neo-Trp, halo-Trp (D or L) or any syntheticaromatic amino acid; Xaa₉ is Pro, Hyp, Gly, an aliphatic amino acidbearing linear or branched saturated hydrocarbon chains such as Leu (Dor L), Ile and Val or non-natural derivatives of the aliphatic aminoacid; Xaa₁₀ is Thr, Ser, g-Thr, g-Ser, Ala, an aliphatic amino acidbearing linear or branched saturated hydrocarbon chains such as Leu (Dor L), Ile and Val or non-natural derivatives of the aliphatic aminoacid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Trp (D or L),neo-Trp, halo-Trp (D or L) or any synthetic aromatic amino acid; Xaa₁₁is Pro, Hyp, Ser, Thr, g-Hyp, g-Ser, g-Thr or any hydroxylated aminoacid; Xaa₁₂ is an aliphatic amino acid bearing linear or branchedsaturated hydrocarbon chains such as Leu (D or L), Ile and Val ornon-natural derivatives of the aliphatic amino acid, Phe, Tyr, meta-Tyr,ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr, Lys, Arg, ornithine, homo-Lys, homoarginine,nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or anysynthetic basic amino acid; Xaa₁₃ is Pro, Hyp, an aliphatic amino acidbearing linear or branched saturated hydrocarbon chains such as Leu (Dor L), Ile and Val or non-natural derivatives of the aliphatic aminoacid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys,N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any syntheticbasic amino acid; Xaa₁₄ is Gly, His, Lys, Arg, ornithine, homo-Lys,homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys,N,N′,N″-trimethyl-Lys or any synthetic basic amino acid; Xaa₁₅ isdes-Xaa₁₅, Ser, Thr, g-Ser, g-Thr, Val, Asn, Phe, Tyr, meta-Tyr,ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr, Trp (D or L), neo-Trp, halo-Trp (D or L) orany synthetic aromatic amino acid; Xaa₁₆ is Met, Nle, an aliphatic aminoacid bearing linear or branched saturated hydrocarbon chains such as Leu(D or L), Ile and Val or non-natural derivatives of the aliphatic aminoacid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Trp (D or L),neo-Trp, halo-Tip (D or L), any synthetic aromatic amino acid, Arg, Lys,ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any synthetic basic aminoacid; Xaa₁₇ is Pro, Hyp, Ser, Thr, g-Hyp, g-Ser, g-Thr, any hydroxylatedamino acid, Ala, Met, Leu, Glu, Gla, Gln, Asp, Asn, any synthetic acidicamino acid, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, His or Gly; Xaa₁₈is Gly, Ala, Ser, Thr, Pro, Hyp, g-Ser, g-Thr, g-Hyp, Glu, Asn or Gln;Xaa₁₉ is Leu, Gly, Asn, Trp (D or L), neo-Trp or halo-Trp (D or L);Xaa₂₀ is des-Xaa₂₀, Leu or Trp (D or L), neo-Trp or halo-Trp (D or L);Xaa₂₁ is des-Xaa₂₁ or an aliphatic amino acid bearing linear or branchedsaturated hydrocarbon chains such as Leu (D or L), Ile and Val ornon-natural derivatives of the aliphatic amino acid; Xaa₂₂ is des-Xaa₂₂,Gly, Met, Nle, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Trp (D or L),neo-Trp, halo-Trp (D or L) or any synthetic aromatic amino acid; Xaa₂₃is des-Xaa₂₃, Pro, Hyp, Ala, an aliphatic amino acid bearing linear orbranched saturated hydrocarbon chains such as Leu (D or L), Ile and Valor non-natural derivatives of the aliphatic amino acid, Phe, Tyr,meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr, Trp (D or L), neo-Trp, halo-Trp (D or L) orany synthetic aromatic amino acid; Xaa₂₄ is Ala, an aliphatic amino acidbearing linear or branched saturated hydrocarbon chains such as Leu (Dor L), Ile and Val or non-natural derivatives of the aliphatic aminoacid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Trp (D or L),neo-Trp, halo-Trp (D or L) or any synthetic aromatic amino acid; Xaa₂₅is Ala, an aliphatic amino acid bearing linear or branched saturatedhydrocarbon chains such as Leu (D or L), Ile and Val or non-naturalderivatives of the aliphatic amino acid, Tyr, meta-Tyr, ortho-Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr or Phe; Xaa₂₆ is an aliphatic amino acid bearing linear orbranched saturated hydrocarbon chains such as Leu (D or L), Ile and Valor non-natural derivatives of the aliphatic amino acid; Xaa₂₇ isdes-Xaa₂₇, Asp, Glu, Gla, Pro, Hyp, Ser, Thr, g-Hyp, g-Ser, g-Ser or anysynthetic hydroxylated amino acid; Xaa₂₈ is des-Xaa₂₈, Glu, Gla, Gln,Asp, Asn, any synthetic acidic amino acid, Lys, Arg, ornithine,homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys,N,N′,N″-trimethyl-Lys, any synthetic basic amino acid, Ile, Ser, Thr,g-Ser or g-Thr; Xaa₂₉ is des-Xaa₂₉, Pro, Hyp, Tyr, meta-Tyr, ortho-Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr ornitro-Tyr; Xaa₃₀ is des-Xaa₃₀ or Phe, with the proviso that the peptideis not MrVIA/B as defined below. The Cys residues may be in D or Lconfiguration and may optionally be substituted with homocysteine (D orL). The Tyr residues may be substituted with ¹²⁵I-Tyr or with the3-hydroxyl or 2-hydroxyl isomers and corresponding O-sulpho- andO-phospho-derivatives. The acidic amino acid residues may be substitutedwith any synthetic acidic amino acid, e.g., tetrazolyl derivatives ofGly and Ala. The nonnatural derivatives of the aliphatic amino acidsinclude those synthetic derivatives bearing non-natural aliphaticbranched or linear side chairs C_(n)H_(2n+2) up to and including n=8.The halogen is iodo, chloro, fluoro or bromo; preferably iodo forhalogen substituted-Tyr and bromo for halogen-substituted Trp.

[0021] MrVIA/B has the sequence:Ala-Cys-Xaa₃₁-Lys-Lys-Trp-Glu-Tyr-Cys-Ile-Val-Xaa₃₂-Ile-Xaa₃₃-Gly-Phe-Xaa₃₄-Tyr-Cys-Cys-Xaa₃₂-Gly-Leu-Ile-Cys-Gly-Xaa₃₂-Phe-Val-Cys-Val,wherein Xaa₃₁ is Arg or Ser, Xaa₃₂ is Pro or hydroxy-Pro, Xaa₃₃ is Ileor Leu and Xaa₃₄ is lie or Val (SEQ ID NO:2).

[0022] The present invention is also directed to novel specificconotoxin peptides within general formula I having the formulas:

Ala-Cys-Arg-Gln-Xaa₁-Xaa₂-Xaa₃-Phe-Cys-Leu-Val-Xaa₄-Ile-Ile-Gly-Xaa₂-Ile-Xaa₂-Cys-Cys-Ala-Gly-Leu-Ile-Cys-Gly-Xaa₄-Phe-Val-Cys-Leu(SEQ ID NO:3);

Xaa₄-Thr-Cys-Leu-Xaa₁-Gln-Asp-Xaa₁-Phe-Cys-Ile-Ile-Xaa₄-Leu-Ile-Gly-Thr-Leu-Xaa₂-Cys-Cys-Ser-Gly-Leu-Ile-Cys-Gly-Phe-Phe-Val-Cys-Val-Xaa₄-Xaa₁-Xaa₄-Phe(SEQ ID NO:4);

Asp-Cys-Xaa₃-Ala-Asp-Gly-Ala-Phe-Cys-Gly-Ile-Xaa₄-Ile-Val-Xaa₁-Asn-Xaa₅-Met-Cys-Cys-Ser-Asn-Leu-Cys-Ile-Phe-Ala-Cys-Val-Xaa₄-Xaa₃-Xaa₂(SEQ ID NO:5);

Asp-Cys-His-Xaa₃-Arg-Xaa₅-Asp-Xaa₅-Cys-Xaa₄-Ala-Ser-Ile-Leu-Gly-Val-Ile-Xaa₂-Cys-Cys-Xaa₃-Gly-Leu-Ile-Cys-Phe-Ile-Ala-Phe-Cys-Ile(SEQ ID NO:6);

Asp-Cys-Gln-Xaa₃-Xaa₁-Xaa₅-Xaa₃-Phe-Cys-Ile-Val-Xaa₄-Ile-Leu-Gly-Phe-Val-Xaa₂-Cys-Cys-Xaa₄-Gly-Leu-Ile-Cys-Gly-Xaa₄-Phe-Val-Cys-Val-Asp-Ile(SEQ ID NO:7);

Xaa₄-Thr-Cys-Val-Ser-Xaa₂-Asn-Val-Phe-Cys-Gly-Val-Xaa₄-Leu-Val-Gly-Thr-Xaa₂-Leu-Cys-Cys-Ser-Gly-Leu-Val-Cys-Leu-Val-Val-Cys-Ile(SEQ ID NO:8);

Cys-Arg-Xaa₄-Arg-Gly-Met-Phe-Cys-Gly-Phe-Xaa₄-Xaa₄-Xaa₄-Gly-Xaa₄-Xaa₂-Cys-Cys-Asn-Gly-Xaa₅-Cys-Phe-Phe-Val-Cys-Ile(SEQ ID NO:9);

Arg-Xaa₅-Cys-Ala-Leu-Asp-Gly-Xaa₃-Leu-Cys-Ile-Ile-Xaa₄-Val-Ile-Gly-Ser-Ile-Phe-Cys-Cys-His-Gly-Ile-Cys-Met-Ile-Xaa₂-Cys-Val(SEQ ID NO:10);

Asp-Cys-Arg-Xaa₄-Val-Gly-Gln-Xaa₂-Cys-Gly-Ile-Xaa₄-Xaa₂-Xaa₁-His-Asn-Xaa₅-Arg-Cys-Cys-Ser-Gln-Leu-Cys-Ala-Ile-Ile-Cys-Val-Ser(SEQ ID NO:11);

Gly-Cys-Leu-Asp-Xaa₄-Gly-Xaa₂-Phe-Cys-Gly-Thr-Xaa₄-Phe-Leu-Gly-Ala-Xaa₂-Cys-Cys-Gly-Gly-Ile-Cys-Leu-Ile-Val-Cys-Ile-Xaa₃-Thr(SEQ ID NO:12),

Asp-Cys-Xaa₃-Ala-Asp-Gly-Ala-Phe-Cys-Gly-Ile-Xaa₄-Ile-Val-Xaa₁-Asn-Xaa₅-Met-Cys-Cys-Ser-Asn-Leu-Cys-Ile-Phe-Ala-Cys-Val-Xaa₄-Xaa₃-Xaa₂(SEQ ID NO:13);

Asp-Cys-Xaa₃-Ala-Asp-Gly-Ala-Phe-Cys-Gly-Ile-Xaa₄-Thr-Val-Xaa₁-Asn-Xaa₅-Met-Cys-Cys-Ser-Asn-Leu-Cys-Ile-Phe-Ala-Cys-Val-Xaa₄-Xaa₃-Xaa₂(SEQ ID NO:14);

Asp-Cys-Gln-Xaa₃-Xaa₃-Xaa₅-Xaa₃-Phe-Cys-Ile-Val-Xaa₄-Ile-Leu-Gly-Phe-Val-Xaa₂-Cys-Cys-Xaa₄-Gly-Leu-Ile-Cys-Gly-Xaa₄-Phe-Val-Cys-Val(SEQ ID NO:15);

Ala-Cys-Arg-Gln-Xaa₁-Xaa₂-Xaa₃-Phe-Cys-Leu-Val-Xaa₄-Ile-Ile-Gly-Xaa₂-Ile-Xaa₂-Cys-Cys-Ala-Gly-Leu-Ile-Cys-Gly-Xaa₄-Phe-Val-Cys-Leu(SEQ ID NO:16);

Xaa₄-Thr-Cys-Leu-Xaa₁-Gln-Asp-Xaa₁-Phe-Cys-Ile-Ile-Xaa₄-Leu-Ile-Gly-Thr-Leu-Xaa₂-Cys-Cys-Ser-Gly-Leu-Ile-Cys-Gly-Phe-Phe-Val-Cys-Val-Xaa₄-Xaa₁-Xaa₄-Phe(SEQ ID NO:17);

Xaa₄-Thr-Cys-Val-Ser-Xaa₂-Asn-Val-Phe-Cys-Gly-Val-Xaa₄-Leu-Val-Gly-Thr-Xaa₂-Leu-Cys-Cys-Ser-Gly-Leu-Val-Cys-Leu-Val-Val-Cys-Ile(SEQ ID NO:18);

Asp-Cys-His-Xaa₃-Arg-Xaa₅-Asp-Xaa₅-Cys-Xaa₄-Ala-Ser-Ile-Leu-Gly-Val-Ile-Xaa₂-Cys-Cys-Xaa₃-Gly-Leu-Ile-Cys-Phe-Ile-Ala-Phe-Cys-Ile(SEQ ID NO:19); and

Asp-Cys-Gln-Xaa₃-Xaa₁-Xaa₅-Xaa₃-Phe-Cys-Ile-Val-Xaa₄-Ile-Leu-Gly-Phe-Val-Xaa₂-Cys-Cys-Xaa₄-Gly-Leu-Ile-Cys-Gly-Xaa₄-Phe-Val-Cys-Val-Asp-Ile(SEQ ID NO:20),

[0023] wherein Xaa₁ is Lys, N-methy-Lys, N,N-dimethyl-Lys orN,N,N-trimethyl-Lys; Xaa₂ is Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; Xaa₃ is Glu orgamma-carboxy-Glu (Gla); Xaa₄ is Pro or hydroxy-Pro; Xaa₅ is Trp orhalo-Trp; and the C-terminus contains a carboxyl or amide group. Thehalo is preferably chlorine or iodine, more preferably iodine. Inaddition, the Arg residues may be substituted by Lys, ornithine,homoargine, nor-Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lysor any synthetic basic amino acid; the Xaa₁ residues may be substitutedby Arg, ornithine, homoargine, nor-Lys, or any synthetic basic aminoacid; the Tyr residues may be substituted with any synthetic hydroxycontaining amino acid; the Ser residues may be substituted with Thr orany synthetic hydroxylated amino acid; the Thr residues may besubstituted with Ser or any synthetic hydroxylated amino acid; the Pheand Trp residues may be substituted with any synthetic aromatic aminoacid; and the Asn, Ser, Thr or Hyp residues may be glycosylated. The Cysresidues may be in D or L configuration and may optionally besubstituted with homocysteine (D or L). The Tyr residues may also besubstituted with ¹²⁵I-Tyr or with the 3-hydroxyl or 2-hydroxyl isomers(meta-Tyr or ortho-Tyr, respectively) and corresponding O-sulpho-andO-phospho-derivatives. The acidic amino acid residues may be substitutedwith any synthetic acidic amino acid, e.g., tetrazolyl derivatives ofGly and Ala. The aliphatic amino acids may be substituted by syntheticderivatives bearing non-natural aliphatic branched or linear side chainsC_(n)H_(2n+2) up to and including n=8.

[0024] More specifically, the present invention is directed to thefollowing μO-conopeptides within general formula I:

MrVIA: SEQ ID NO:2, wherein Xaa₃₀ is Arg, Xaa₃₁ is Ile and Xaa₃₂ is Ile;

MrVIB: SEQ ID NO:2, wherein Xaa₃₀ is Ser, Xaa₃₁ is Leu and Xaa₃₂ is Val;

A657: SEQ ID NO:3, wherein Xaa₁ is Lys, Xaa₂ is Tyr, Xaa₃ is Glu andXaa₄ is Pro;

F079: SEQ ID NO:4, wherein Xaa₁ is Lys, Xaa₂ is Tyr and Xaa₄ is Pro;

Ca6.1: SEQ ID NO:5, wherein Xaa₁ is Lys, Xaa₂ is Tyr, Xaa₃ is Glu, Xaa₄is Pro and Xaa₅ is Trp;

Tx6.12: SEQ ID NO:6, wherein Xaa₂ is Tyr, Xaa₃ is Glu, Xaa₄ is Pro andXaa₅ is Trp;

Tx6.13: SEQ ID NO:7, wherein Xaa₁ is Lys, Xaa₂ is Tyr, Xaa₃ is Glu, Xaa₄is Pro and Xaa₅ is Trp;

G28: SEQ ID NO:8, wherein Xaa₂ is Tyr and Xaa₄ is Pro;

F763: SEQ ID NO:9, wherein Xaa₁ is Lys, Xaa₂ is Tyr, Xaa₄ is Pro andXaa₅ is Trp;

F080: SEQ ID NO:10, wherein Xaa₂ is Tyr, Xaa₃ is Glu, Xaa₄ is Pro andXaa₅ is Trp;

F008: SEQ ID NO:11, wherein Xaa₁ is Lys, Xaa₂ is Tyr, Xaa₄ is Pro andXaa₅ is Trp;

G18: SEQ ID NO:12, wherein Xaa₂ is Tyr, Xaa₃ is Glu and Xaa₄ is Pro;

Ca6.1: SEQ ID NO:13, wherein Xaa₁ is Lys, Xaa₂ is Tyr, Xaa₃ is Glu, Xaa₄is Pro and Xaa₅ is Trp;

Ca6.2: SEQ ID NO:14, wherein Xaa₁ is Lys, Xaa₂ is Tyr, Xaa₃ is Glu, Xaa₄is Pro and Xaa₅ is Trp;

Ep6.3: SEQ ID NO:15, wherein Xaa₂ is Tyr, Xaa₃ is Glu, Xaa₄ is Pro andXaa₅ is Trp;

Nb6.1: SEQ ID NO:16, wherein Xaa₁ is Lys, Xaa₂ is Tyr, Xaa₃ is Glu andXaa₄ is Pro;

Ts6.1: SEQ ID NO:17, wherein Xaa₁ is Lys, Xaa₂ is Tyr and Xaa₄ is Pro;

Ts6.5: SEQ ID NO:18, wherein Xaa₂ is Tyr and Xaa₄ is Pro;

Tx6.12: SEQ ID NO:19, wherein Xaa₂ is Tyr, Xaa₃ is Glu, Xaa₄ is Pro andXaa₅ is Trp; and

Tx6.13: SEQ ID NO:20, wherein Xaa₁ is Lys, Xaa₂ is Tyr, Xaa₃ is Glu,Xaa₄ is Pro and Xaa₅ is Trp.

[0025] Examples of synthetic aromatic amino acid include, but are notlimited to, such as nitro-Phe, 4-substituted-Phe wherein the substituentis C₁-C₃ alkyl, carboxyl, hyrdroxymethyl, sulphomethyl, halo, phenyl,—CHO, —CN, —SO₃H and —NHAc. Examples of synthetic hydroxy containingamino acid, include, but are not limited to, such as4-hydroxymethyl-Phe, 4-hydroxyphenyl-Gly, 2,6-dimethyl-Tyr and5-amino-Tyr. Examples of synthetic basic amino acids include, but arenot limited to, N-1-(2-pyrazolinyl)-Arg, 2-(4-piperinyl)-Gly,2-(4-piperinyl)-Ala, 2-[3-(2S)pyrrolininyl)-Gly and2-[3-(2S)pyrrolininyl)-Ala. These and other synthetic basic amino acids,synthetic hydroxy containing amino acids or synthetic aromatic aminoacids are described in Building Block Index, Version 3.0 (1999 Catalog,pages 4-47 for hydroxy containing amino acids and aromatic amino acidsand pages 66-87 for basic amino acids; see alsohttp://www.amino-acids.com), incorporated herein by reference, by andavailable from RSP Amino Acid Analogues, Inc., Worcester, Mass. Examplesof synthetic acid amino acids include those derivatives bearing acidicfunctionality, including carboxyl, phosphate, sulfonate and synthetictetrazolyl derivatives such as described by Ornstein et al. (1993) andin U.S. Pat. No. 5,331,001, each incorporated herein by reference.

[0026] Optionally, in the peptides of general formula I and the specificpeptides described above, the Asn residues may be modified to contain anN-glycan and the Ser, Thr and Hyp residues may be modified to contain anO-glycan (e.g., g-N, g-S, g-T and g-Hyp). In accordance with the presentinvention, a glycan shall mean any N-, S- or O-linked mono-, di-, tri-,poly- or oligosaccharide that can be attached to any hydroxy, amino orthiol, group of natural or modified amino acids by synthetic orenzymatic methodologies known in the art. The monosaccharides making upthe glycan can include D-allose, D-altrose, D-glucose, D-mannose,D-gulose, D-idose, D-galactose, D-talose, D-galactosamine,D-glucosamine, D-N-acetyl-glucosamine (GlcNAc), D-N-acetyl-galactosamine(GalNAc), D-fucose or D-arabinose. These saccharides may be structurallymodified, e.g., with one or more O-sulfate, O-phosphate, O-acetyl oracidic groups, such as sialic acid, including combinations thereof. Thegylcan may also include similar polyhydroxy groups, such asD-penicillamine 2,5 and halogenated derivatives thereof or polypropyleneglycol derivatives. The glycosidic linkage is beta and 1-4 or 1-3,preferably 1-3. The linkage between the glycan and the amino acid may bealpha or beta, preferably alpha and is 1-.

[0027] Core O-glycans have been described by Van de Steen et al. (1998),incorporated herein by reference. Mucin type O-linked oligosaccharidesare attached to Ser or Thr (or other hydroxylated residues of thepresent peptides) by a GalNAc residue. The monosaccharide buildingblocks and the linkage attached to this first GalNAc residue define the“core glycans,” of which eight have been identified. The type ofglycosidic linkage (orientation and connectivities) are defined for eachcore glycan. Suitable glycans and glycan analogs are described furtherin U.S. Ser. No. 09/420,797 filed Oct. 19, 1999 and in PCT ApplicationNo. PCT/US99/24380 filed Oct. 19, 1999 (PCT Published Application No. WO00/23092), each incorporated herein by reference. A preferred glycan isGal(β1→3)GalNAc(α1→).

[0028] Optionally, in the peptides of general formula I and the specificpeptides described above, pairs of Cys residues may be replaced pairwisewith isoteric lactam or ester-thioether replacements, such as Ser/(Gluor Asp), Lys/(Glu or Asp) or Cys/Ala combinations. Sequential couplingby known methods (Barnay et al., 2000; Hruby et al., 1994; Bitan et al.,1997) allows replacement of native Cys bridges with lactam bridges.Thioether analogs may be readily synthesized using halo-Ala residuescommercially available from RSP Amino Acid Analogues.

[0029] The present invention is further directed to derivatives of theabove peptides and peptide derivatives which are acylic permutations inwhich the cyclic permutants retain the native bridging pattern of nativetoxin. See Craik et al. (2001).

[0030] The present invention is also directed to the identification ofthe nucleic acid sequences encoding these peptides and their propeptidesand the identication of nucleic acid sequences of additional relatedμO-conopeptides.

[0031] The present invention is further directed to a method ofreducing/alleviating/decreasing the perception of pain by a subject orfor inducing analgesia, particularly local analgesia, in a subjectcomprising administering to the subject an effective amount of thepharmaceutical composition comprising a therapeutically effective amountof a μO-conotoxin peptide described herein or a pharmaceuticallyacceptable salt or solvate thereof, including MrVIA and MrVIB. Thepresent invention is also directed to a pharmaceutic al compositioncomprising a therapeutically effective amount of a μO-conotoxin peptidedescribed herein or a pharmaceutically acceptable salt or solvatethereof and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE FIGURES

[0032]FIG. 1 shows μO-conopeptide MrVIB inhibits skin flinch sensitivityin the Guinea pig intracutaneous wheal assay with greater potency thanlidocaine or bupivacaine. Data represent the number of flinches observedafter 36 pin pricks in a 30 minutes test period. Each point representsthe mean of at least three observations.

[0033]FIG. 2 shows μO-conopeptide MrVIB produces a long-lastinginhibition of skin flinch sensitivity relative to either lidocaine orbupivacaine in the Guinea pig intracutaneous wheal assay. Data representthe percentage of flinches observed out of six total at each time point.Each point represents the mean of at least three observations.

DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention is directed to the new μO-conopeptides,their coding sequences and their propeptides and to the use ofμO-conopeptides as a local anesthetic for treating pain. TheμO-conopeptides have long lasting anesthetic activity and areparticularly useful for spinal anesthesia, either administered acutelyfor post-operative pain or via an intrathecal pump for severe chronicpain situations or for treatment of pain in epithelial tissue.

[0035] The present invention, in another aspect, relates to apharmaceutical composition comprising an effective amount of a conotoxinpeptide described herein or a pharmaceutically acceptable salt orsolvate thereof. Such a pharmaceutical composition has the capability ofacting as analgesic agents.

[0036] The present invention also provides for a method provides localanesthesia to a patient having pain. In one embodiment, the pain resultsfrom surgical or medical procedures, and the compounds are administeredto the central nervous system (CNS), e.g. to the spine for spinalanalgesia. In a second embodiment, the pain is in an epithelial tissueregion associated with damage or loss of epithelial tissue as a resultof, for example, plastic surgery, canker sores, burns, sore throats,genital lesions, upper or lower gastrointestinal bronchoscopy orendoscopy, intubation, dermatologic abrasions, scratched corneas orchemical skin peels, and the compounds are administered to alleviate theassociated pain. The μO-conopeptides administered in accordance with themethod of the invention are also beneficial in relieving pain of thecorneas.

[0037] The conotoxin peptides described herein are sufficiently small tobe chemically synthesized. General chemical syntheses for preparing theforegoing conotoxin peptides are described hereinafter. Various ones ofthe conotoxin peptides can also be obtained by isolation andpurification from specific Conus species using the technique describedin U.S. Pat. No. 4,447,356 (Olivera et al., 1984), the disclosure ofwhich is incorporated herein by reference.

[0038] Although the conotoxin peptides of the present invention can beobtained by purification from cone snails, because the amounts ofconotoxin peptides obtainable from individual snails are very small, thedesired substantially pure conotoxin peptides are best practicallyobtained in commercially valuable amounts by chemical synthesis usingsolid-phase strategy. For example, the yield from a single cone snailmay be about 10 micrograms or less of conotoxin peptide. By“substantially pure” is meant that the peptide is present in thesubstantial absence of other biological molecules of the same type; itis preferably present in an amount of at least about 85% purity andpreferably at least about 95% purity. Chemical synthesis of biologicallyactive conotoxin peptides depends of course upon correct determinationof the amino acid sequence.

[0039] The conotoxin peptides can also be produced by recombinant DNAtechniques well known in the art. Such techniques are described bySambrook et al. (1989). The peptides produced in this manner areisolated, reduced if necessary, and oxidized to form the correctdisulfide bonds.

[0040] One method of forming disulfide bonds in the peptides of thepresent invention is the air oxidation of the linear peptides forprolonged periods under cold room temperatures or at room temperature.This procedure results in the creation of a substantial amount of thebioactive, disulfide-linked peptides. The oxidized peptides arefractionated using reverse-phase high performance liquid chromatography(HPLC) or the like, to separate peptides having different linkedconfigurations. Thereafter, either by comparing these fractions with theelution of the native material or by using a simple assay, theparticular fraction having the correct linkage for maximum biologicalpotency is easily determined. However, because of the dilution resultingfrom the presence of other fractions of less biopotency, a somewhathigher dosage may be required.

[0041] The peptides are synthesized by a suitable method, such as byexclusively solid-phase techniques, by partial solid-phase techniques,by fragment condensation or by classical solution couplings.

[0042] In conventional solution phase peptide synthesis, the peptidechain can be prepared by a series of coupling reactions in whichconstituent amino acids are added to the growing peptide chain in thedesired sequence. Use of various coupling reagents, e.g.,dicyclohexylcarbodiimide or diisopropylcarbonyldimidazole, variousactive esters, e.g., esters of N-hydroxyphthalimide orN-hydroxy-succinimide, and the various cleavage reagents, to carry outreaction in solution, with subsequent isolation and purification ofintermediates, is well known classical peptide methodology. Classicalsolution synthesis is described in detail in the treatise, “Methoden derOrganischen Chemie (Houben-Weyl): Synthese von Peptiden,” (1974).Techniques of exclusively solid-phase synthesis are set forth in thetextbook, “Solid-Phase Peptide Synthesis,” (Stewart and Young, 1969),and are exemplified by the disclosure of U.S. Pat. No. 4,105,603 (Val,et al., 1978). The fragment condensation method of synthesis isexemplified in U.S. Pat. No. 3,972,859 (1976). Other available synthesesare exemplified by U.S. Pat. No. 3,842,067 (1974) and U.S. Pat. No.3,862,925 (1975). The synthesis of peptides containing γ-carboxyglutamicacid residues is exemplified by Rivier et al. (1987), Nishiuchi et al.(1993) and Zhou et al. (1996).

[0043] Common to such chemical syntheses is the protection of the labileside chain groups of the various amino acid moieties with suitableprotecting groups which will prevent a chemical reaction from occurringat that site until the group is ultimately removed. Usually also commonis the protection of an α-amino group on an amino acid or a fragmentwhile that entity reacts at the carboxyl group, followed by theselective removal of the α-amino protecting group to allow subsequentreaction to take place at that location. Accordingly, it is common that,as a step in such a synthesis, an intermediate compound is producedwhich includes each of the amino acid residues located in its desiredsequence in the peptide chain with appropriate side-chain protectinggroups linked to various ones of the residues having labile side chains.

[0044] As far as the selection of a side chain amino protecting group isconcerned, generally one is chosen which is not removed duringdeprotection of the α-amino groups during the synthesis. However, forsome amino acids, e.g., His, protection is not generally necessary. Inselecting a particular side chain protecting group to be used in thesynthesis of the peptides, the following general rules are followed: (a)the protecting group preferably retains its protecting properties and isnot split off under coupling conditions, (b) the protecting group shouldbe stable under the reaction conditions selected for removing theα-amino protecting group at each step of the synthesis, and (c) the sidechain protecting group must be removable, upon the completion of thesynthesis containing the desired amino acid sequence, under reactionconditions that will not undesirably alter the peptide chain.

[0045] It should be possible to prepare many, or even all, of thesepeptides using recombinant DNA technology. However, when peptides arenot so prepared, they are preferably prepared using the Merrifieldsolid-phase synthesis, although other equivalent chemical synthesesknown in the art can also be used as previously mentioned. Solid-phasesynthesis is commenced from the C-terminus of the peptide by coupling aprotected α-amino acid to a suitable resin. Such a starting material canbe prepared by attaching an α-amino-protected amino acid by an esterlinkage to a chloromethylated resin or a hydroxymethyl resin, or by anamid e bond to a benzhydrylamine (BHA) resin orparamethylbenzhydrylamine NBHA) resin. Preparation of the hydroxymethylresin is described by Bodansky et al. (1966). Chloromethylated resinsare commercially available from Bio Rad Laboratories (Richmnond, Calif.)and from Lab. Systems, Inc. The preparation of such a resin is describedby Stewart and Young (1969). BHA and MBHA resin supports arecommercially available, and are generally used when the desiredpolypeptide being synthesized has an unsubstituted amide at theC-terminus. Thus, solid resin supports may be any of those known in theart, such as one having the formulae —O—CH₂—resin support, —NH BHA resinsupport, or —NH—MBHA resin support. When the unsubstituted amide isdesired, use of a BHA or MBHA resin is preferred, because cleavagedirectly gives the amide. In case the N-methyl amide is desired, it canbe generated from an N-methyl BHA resin. Should other substituted amidesbe desired, the teaching of U.S. Pat. No. 4,569,967 (Kornreich et al.,1986) can be used, or should still other groups than the free acid bedesired at the C-terminus, it may be preferable to synthesize thepeptide using classical methods as set forth in the Houben-Weyl text(1974).

[0046] The C-terminal amino acid, protected by Boc or Fmoc and by aside-chain protecting group, if appropriate, can be first coupled to achloromethylated resin according to the procedure set forth in Horiki etal. (1978), using KF in DMF at about 60° C. for 24 hours with stirring,when a peptide having free acid at the C-terminus is to be synthesized.Following the coupling of the BOC-protected amino acid to the resinsupport, the α-amino protecting group is removed, as by usingtrifluoroacetic acid (TFA) in methylene chloride or TFA alone. Thedeprotection is carried out at a temperature between about 0° C. androom temperature. Other standard cleaving reagents, such as HCl indioxane, and conditions for removal of specific α-amino protectinggroups may be used as described in Schroder & Lubke (1965).

[0047] After removal of the α-amino-protecting group, the remainingα-amino- and side chain-protected amino acids are coupled step-wise inthe desired order to obtain the intermediate compound definedhereinbefore, or as an alternative to adding each amino acid separatelyin the synthesis, some of them may be coupled to one another prior toaddition to the solid phase reactor. Selection of an appropriatecoupling reagent is within the skill of the art. Particularly suitableas a coupling reagent is N,N′-dicyclohexylcarbodiimide (DCC, DIC, HBTU,HATU, TBTU in the presence of HoBt or HoAt).

[0048] The activating reagents used in the solid phase synthesis of thepeptides are well known in the peptide art. Examples of suitableactivating reagents are carbodiimides, such asN,N′-diisopropylcarbodiimide andN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide. Other activatingreagents and their use in peptide coupling are described by Schroder &Lubke (1965) and Kapoor (1970).

[0049] Each protected amino acid or amino acid sequence is introducedinto the solid-phase reactor in about a twofold or more excess, and thecoupling may be carried out in a medium of dimethylformamide(DMF):CH₂Cl₂ (1:1) or in DMF or CH₂Cl₂ alone. In cases whereintermediate coupling occurs, the coupling procedure is repeated beforeremoval of the α-amino protecting group prior to the coupling of thenext amino acid. The success of the coupling reaction at each stage ofthe synthesis, if performed manually, is preferably monitored by theninhydrin reaction, as described by Kaiser et al. (1970). Couplingreactions can be performed automatically, as on a Beckman 990 automaticsynthesizer, using a program such as that reported in Rivier et al.(1978).

[0050] After the desired amino acid sequence has been completed, theintermediate peptide can be removed from the resin support by treatmentwith a reagent, such as liquid hydrogen fluoride or TFA (if using Fmocchemistry), which not only cleaves the peptide from the resin but alsocleaves all remaining side chain protecting groups and also the α-aminoprotecting group at the N-terminus if it was not previously removed toobtain the peptide in the form of the free acid. If Met is present inthe sequence, the Boc protecting group is preferably first removed usingtrifluoroacetic acid (TFA)/ethanedithiol prior to cleaving the peptidefrom the resin with HF to eliminate potential S-alkylation. When usinghydrogen fluoride or TFA for cleaving, one or more scavengers such asanisole, cresol, dimethyl sulfide and methylethyl sulfide are includedin the reaction vessel.

[0051] Cyclization of the linear peptide is preferably affected, asopposed to cyclizing the peptide while a part of the peptido-resin, tocreate bonds between Cys residues. To effect such a disulfide cyclizinglinkage, fully protected peptide can be cleaved from a hydroxymethylatedresin or a chloromethylated resin support by ammonolysis, as is wellknown in the art, to yield the fully protected amide intermediate, whichis thereafter suitably cyclized and deprotected. Alternatively,deprotection, as well as cleavage of the peptide from the above resinsor a benzhydrylamine (BHA) resin or a methylbenzhydrylamine (MBHA), cantake place at 0° C. with hydrofluoric acid (HF) or TFA, followed byoxidation as described above.

[0052] The peptides are also synthesized using an automatic synthesizer.Amino acids are sequentially coupled to an MBHA Rink resin (typically100 mg of resin) beginning at the C-terminus using an Advanced Chemtech357 Automatic Peptide Synthesizer. Couplings are carried out using1,3-diisopropylcarbodimide in N-methylpyrrolidinone (NMP) or by2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU) and diethylisopro-pylethylamine (DIEA). The FMOC protecting groupis removed by treatment with a 20% solution of piperidine indimethylformamide(DMF). Resins are subsequently washed with DMF (twice),followed by methanol and NMP.

[0053] Additional conotoxin peptides are identified by cloning byreverse transcription-polymerase chain reaction (RT-PCR) from cone snailvenom duct mRNA. The PCR primers are based on the DNA sequences codingfor the precursor peptides of the “O-Superfamily” as described herein.RT-PCR of venom duct mRNA produces a product of about 250-300nucleotides in Conus species that express conotoxin genes. The PCRproduct is then cloned into a plasmid vector and individual clones aresequenced to determine the sequence of various conotoxin genes.Alternatively, cDNA libraries are prepared from Conus venom duct usingconventional techniques. DNA from single clones is amplified byconventional techniques using primers which correspond approximately tothe M13 universal priming site and the M13 reverse universal primingsite. Clones having a size of approximately 250 nucleotides aresequenced and screened for similarity in sequence to the propeptidedescribed herein. In this manner, conotoxins having the basic structureand activity described herein are cloned from many Conus species.

[0054] Muteins, analogs or active fragments (collectively referred toherein as derivatives) of μO-conopeptides are also contemplated for useas local anesthetics. See, e.g., Hammerland et al. (1992). Derivativemuteins, analogs or active fragments of μO-conopeptides may besynthesized according to known techniques, including conservative aminoacid substitutions, such as outlined in U.S. Pat. Nos. 5,545,723;5,534,615 and 5,364,769. The derivative muteins, analogs or activefragments may be conveniently assayed for activity by using a hindlimbparalysis test such as described in Example 2 or a local anesthetic testsuch as described in Example 3.

[0055] A variety of peptides from Conus target sodium channels.μ-Conopeptides (i.e., GVIA) block sodium channels expressed by musclecells (Olivera et al., 1990). δ-Conopeptides (i.e., GmVIA) delay theinactivation of neuronal sodium channels (Olivera et al., 1990). Anotherclass of conopeptide (i.e., μ-PnIVA and μ-PnIVB; unfortunately alsocalled μ but having a distinct cysteine framework from that which isconsidered a μ-conopeptide) blocks sodium channels in molluscan neurons,but has no effect on sodium currents in bovine chromaffin cells or inrat brain synaptosomes (Fainzilber et al., 1995). Finally, theμO-conopeptides (MrVIA and MrVIB) block mammalian sodium channels(McIntosh et al., 1995).

[0056] Since the μO-conopeptides have been shown to have a slow andincomplete washout from Xenopus oocytes expressing cloned rat type IIsodium channels (Terlau et al., 1996), the present invention examinedwhether the μO-conopeptides might represent a candidate for along-lasting local anesthetic.

[0057] Thus, the present invention is directed to a method for inducinglocal analgesia by administering the μO-conopeptides described herein.In one embodiment, the pain results from surgical or medical procedures,and the compounds are administered to the central nervous system (CNS),e.g. to the spine for spinal analgesia. Thus, the μO-conopeptidesadministered in accordance with the method of the invention arebeneficial for spinal anesthesia, administered either acutely forpost-operative pain or via an intrathecal pump for severe chronic painsituations.

[0058] In a second embodiment, μO-conopeptides are used to provide localanesthesia for pain associated with any epithelial tissue region in asubject, for example, pain associated with epithelial ulcers, such as acanker sore or genital lesions. Canker sores can occur alone or ingroups on the inside of the cheek or lip or underneath the tongue.Severely affected people have continuously recurring ulcers which lastfor one to two weeks (Clayman). Genital ulcers are usually caused bysexually transmitted diseases, including herpes and syphilis. The earlystages of syphilis are characterized by a hard chancre, a painful ulcerwhere bacteria has penetrated the skin. This may be followed by shallow,elongated ulcers once the chancre has healed. Such ulcers are painful.Genital ulceration may also be a side effect of drugs taken orally orcaused by solutions applied to genital warts. Pain in epithelial tissueis also caused by bums. Bums affecting the epidermal layer are usuallyassociated with pain, restlessness and fever. Treatment of such a burnin accordance with the method of the invention can provide relief fromthe attendant pain. Pain as a result of damage to or loss of epithelialtissue is also associated with other conditions and procedures, such assore throats and plastic surgery, for example carbon dioxide lasersurgery to remove for skin resurfacing and removal of wrinkles(Rosenberg et al., 1996), burns, genital lesions, upper or lowergastrointestinal bronchoscopy or endoscopy, intubation, dermatologicabrasions, scratched corneas or chemical skin peels. The μO-conopeptidesadministered in accordance with the method of the invention arebeneficial in relieving pain associated with such damaged tissues. TheμO-conopeptides administered in accordance with the method of theinvention are also beneficial in relieving pain of the corneas.

[0059] Pharmaceutical compositions containing a μO-conopeptide orpharmaceutically acceptable salts thereof as the active ingredient(agent) can be prepared according to conventional pharmaceuticalcompounding techniques. See, for example, Remington's PharmaceuticalSciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa.). Typically,a therapeutically effective amount of the active ingredient will beadmixed with a pharmaceutically acceptable carrier. The carrier may takea wide variety of forms depending on the form of preparation desired foradministration, e.g., intravenous, oral or parenteral. The compositionsmay further contain antioxidizing agents, stabilizing agents,preservatives and the like.

[0060] “Pharmaceutical composition” means physically discrete coherentportions suitable for medical administration. “Pharmaceuticalcomposition in dosage unit form” means physically discrete coherentunits suitable for medical administration, each containing a daily doseor a multiple (up to four times) or a sub-multiple (down to a fortieth)of a daily dose of the active compound in association with a carrierand/or enclosed within an envelope. Whether the composition contains adaily dose, or for example, a half, a third or EL quarter of a dailydose, will depend on whether the pharmaceutical composition is to beadministered once or, for example, twice, three times or four times aday, respectively.

[0061] The term “salt”, as used herein, denotes acidic and/or basicsalts, formed with inorganic or organic acids and/or bases, preferablybasic salts. While pharmaceutically acceptable salts are preferred,particularly when employing the compounds of the invention asmedicaments, other salts find utility, for example, in processing thesecompounds, or where non-medicament-type uses are contemplated. Salts ofthese compounds may be prepared by art-recognized techniques.

[0062] Examples of such pharmaceutically acceptable salts include, butare not limited to, inorganic and organic addition salts, such ashydrochloride, sulphates, nitrates or phosphates and acetates,trifluoroacetates, propionates, succinates, benzoates, citrates,tartrates, fumarates, maleates, methane-sulfonates, isothionates,theophylline acetates, salicylates, respectively, or the like. Loweralkyl quaternary ammonium salts and the like are suitable, as well.

[0063] As used herein, the term “pharmaceutically acceptable” carriermeans a non-toxic, inert solid, semi-solid liquid filler, diluent,encapsulating material, formulation auxiliary of any type, or simply asterile aqueous medium, such as saline. Some examples of the materialsthat can serve as pharmaceutically acceptable carriers are sugars, suchas lactose, glucose and sucrose, starches such as corn starch and potatostarch, cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt, gelatin, talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols, such as propyleneglycol, polyols such as glycerin, sorbitol, mannitol and polyethyleneglycol; esters such as ethyl oleate and ethyl laurate, agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline, Ringer's solution; ethyl alcoholand phosphate buffer solutions, as well as other non-toxic compatiblesubstances used in pharmaceutical formulations.

[0064] Wetting agents, emulsifiers and lubricants such as, sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator. Examples ofpharmaceutically acceptable antioxidants include, but are not limitedto, water soluble antioxidants such as ascorbic acid, cysteinehydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite,and the like; oil soluble antioxidants, such as ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),lecithin, propyl gallate, aloha-tocopherol and the like; and the metalchelating agents such as citric acid, ethylenediamine tetraacetic acid(EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

[0065] For oral administration, the compounds can be formulated intosolid or liquid preparations such as capsules, pills, tablets, lozenges,melts, powders, suspensions or emulsions. In preparing the compositionsin oral dosage form, any of the usual pharmaceutical media may beemployed, such as, for example, water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents, suspending agents, andthe like in the case of oral liquid preparations (such as, for example,suspensions, elixirs and solutions); or carriers such as starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like in the case of oral solidpreparations (such as, for example, powders, capsules and tablets).Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe sugar-coated or enteric-coated by standard techniques. The activeagent can be encapsulated to make it stable to passage through thegastrointestinal tract while at the same time allowing for passageacross the blood brain barrier. See for example, WO 96/11698.

[0066] For parenteral administration, the compound may be dissolved in apharmaceutical carrier and administered as either a solution or asuspension. Illustrative of suitable carriers are water, saline,dextrose solutions, fructose solutions, ethanol, or oils of animal,vegetative or synthetic origin. The carrier may also contain otheringredients, for example, preservatives, suspending agents, solubilizingagents, buffers and the like. When the compounds are being administeredintrathecally, they may also be dissolved in cerebrospinal fluid.

[0067] For topical administration, the compound may be formulated as anointment, cream, gel, paste or solution comprising the compound to beadministered in a pharmaceutical acceptable carrier. One means oftopical administration is a transdermal patch containing the compound tobe administered.

[0068] A variety of administration routes are available. The particularmode selected will depend of course, upon the particular drug selected,the severity of the disease state being treated and the dosage requiredfor therapeutic efficacy. The methods of this invention, generallyspeaking, may be practiced using any mode of administration that ismedically acceptable, meaning any mode that produces effective levels ofthe active compounds without causing clinically unacceptable adverseeffects. Such modes of administration include oral, rectal, sublingual,topical, nasal, transdermal or parenteral routes. The term “parenteral”includes subcutaneous, intravenous, epidural, irrigation, intramuscular,release pumps, or infusion.

[0069] For example, administration of the active agent according to thisinvention may be achieved using any suitable delivery means, including:

[0070] (a) pump (see, e.g., Lauer & Hatton (1993), Zimm et al. (1984)and Ettinger et al. (1978));

[0071] (b) microencapsulation (see, e.g., U.S. Pat. Nos. 4,352,883;4,353,888; and 5,084,350);

[0072] (c) continuous release polymer implants (see, e.g., U.S. Pat. No.4,883,666);

[0073] (d) macroencapsulation (see, e.g., U.S. Pat. Nos. 5,284,761,5,158,881, 4,976,859 and 4,968,733 and published PCT patent applicationsWO92/19195, WO 95/05452);

[0074] (e) naked or unencapsulated cell grafts to the CNS (see, e.g.,U.S. Pat. Nos. 5,082,670 and 5,618,531);

[0075] (f) injection, either subcutaneously, intravenously,intra-arterially, intramuscularly, or to other suitable site;

[0076] (g) oral administration, in capsule, liquid, tablet, pill, orprolonged release formulation; or

[0077] (h) topical (see, e.g., U.S. Pat. Nos. 6,046,187 and 6,030,974).

[0078] In one embodiment of this invention, an active agent is delivereddirectly into the CNS, preferably to the brain ventricles, brainparenchyma, the intrathecal space or other suitable CNS location, mostpreferably intrathecally.

[0079] Alternatively, targeting therapies may be used to deliver theactive agent more specifically to certain types of cells, by the use oftargeting systems such as antibodies or cell-specific ligands. Targetingmay be desirable for a variety of reasons, e.g. if the agent isunacceptably toxic, if it would otherwise require too high a dosage, orif it would not otherwise be able to enter target cells.

[0080] The active agents, which are peptides, can also be administeredin a cell based delivery system in which a DNA sequence encoding anactive agent is introduced into cells designed for implantation in thebody of the patient, especially in the spinal cord region. Suitabledelivery systems are described in U.S. Pat. No. 5,550,050 and publishedPCT Application Nos. WO 92/19195, WO 94/25503, WO 95/01203, WO 95/05452,WO 96/02286, WO 96/02646, WO 96/40871, WO 96/40959 and WO 97/12635.Suitable DNA sequences can be prepared synthetically for each activeagent on the basis of the developed sequences and the known geneticcode.

[0081] The active agent is preferably administered in an therapeuticallyeffective amount. By a “therapeutically effective amount” or simply“effective amount” of an active compound is meant a sufficient amount ofthe compound to treat or alleviate pain or to induce analgesia at areasonable benefit/risk ratio applicable to any medical treatment. Theactual amount administered, and the rate and time-course ofadministration, will depend on the nature and severity of the conditionbeing treated. Prescription of treatment, e.g. decisions on dosage,timing, etc., is within the responsibility of general practitioners orspecialists, and typically takes account of the disorder to be treated,the condition of the individual patient, the site of delivery, themethod of administration and other factors known to practitioners.Examples of techniques and protocols can be found in Remington'sPharmaceutical Sciences.

[0082] For the treatment of pain, if the route of administration isdirectly to the CNS, the dosage contemplated is from about 1 ng to about100 mg per day, preferably from about 100 ng to about 10 mg per day,more preferably from about 1 μg to about 100 jig per day. Ifadministered peripherally, the dosage contemplated is somewhat higher,from about 100 ng to about 1000 mg per day, preferably from about 10 μgto about 100 mg per day, more preferably from about 100 μg to about 10mg per day.

[0083] If the μO-conopeptide is delivered by continuous infusion (e.g.,by pump delivery, biodegradable polymer delivery or cell-baseddelivery), then a lower dosage is contemplated than for bolus delivery.

[0084] However, it will be understood that the amount of the activecompound actually administered will be determined by a physician, in thelight of the relevant circumstances including the condition to betreated, the chosen route of administration, the age, weight, andresponse of the individual patient, and the severity of the patient'ssymptoms, and therefore the above dosage ranges are not intended tolimit the scope of the invention in any way. As used herein the terms“pharmaceutical compositions” and “pharmaceutically acceptable” includecompositions and ingredients for both human and veterinary use.

[0085] The present data suggest that μO-conopeptides are extremelypotent and long-lasting local anesthetic agents, most likely due totheir ability to block neuronal sodium channels. Moreover, sinceμO-conopeptides probably act at a site on sodium channels distinct fromother local anesthetics or guanidinium toxins like tetrodotoxin (sincethey are likely to act at an extracellular target, but do compete for[³H]saxitoxin at site I) (Terlau et al., 1996), and probably do notaffect sodium channels in the muscles or heart (since i.p. injection of10 nmol is without effect in mice (McIntosh et al., 1995), thesepeptides lack the untoward side effects of clinically used localanesthetics.

[0086] Despite the high hydrophobicity of these peptides, there is acluster of charged amino acid residues at the amino terminus. Thiscluster of charge, combined with the size of the peptides, probablyresults in poor permeation of the nerve sheath and thus accounts for thepoor efficacy in the tail withdrawal assay. In contrast, when the nervesheath is not a barrier, such as following intrathecal injection orintracutaneous injection, μO-conopeptides are effective andlong-lasting. These facts establish that μO-conopeptides are novelcandidates for spinal anesthesia, either administered acutely forpost-operative pain or via an intrathecal pump for severe chronic painsituations.

[0087] The practice of the present invention employs, unless otherwiseindicated, conventional techniques of chemistry, molecular biology,microbiology, recombinant DNA, genetics, immunology, cell biology, cellculture and transgenic biology, which are within the skill of the art.See, e.g., Maniatis et al., 1982; Sambrook et al., 1989; Ausubel et al.,1992; Glover, 1985; Anand, 1992; Guthrie and Fink, 1991; Harlow andLane, 1988; Jakoby and Pastan, 1979; Nucleic Acid Hybridization (B. D.Hames & S. J. Higgins eds. 1984); Transcription And Translation (B. D.Hames & S. J. Higgins eds. 1984); Culture Of Animal Cells (]R. I.Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells And Enzymes (IRLPress, 1986); B. Perbal, A Practical Guide To Molecular Cloning (1984);the treatise, Methods In Enzymology (Academic Press, Inc., N.Y.); GeneTransfer Vectors For Mammalian Cells (J. H. Miller and M. P. Calos eds.,1987, Cold Spring Harbor Laboratory); Methods In Enzymology, Vols. 154and 155 (Wu et al. eds.), Immunochemical Methods In Cell And MolecularBiology (Mayer and Walker, eds., Academic Press, London, 1987); HandbookOf Experimental Immunology, Volumes I-IV (D. M. Weir and C. C.Blackwell, eds., 1986); Riott, Essential Immunology, 6th Edition,Blackwell Scientific Publications, Oxford, 1988; Hogan et al.,Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press,Cold Spring Harbor, N.Y., 1986).

EXAMPLES

[0088] The present invention is further detailed in the followingExamples, which are offered by way of illustration and are not intendedto limit the invention in any manner. Standard techniques well known inthe art or the techniques specifically described below are utilized.

Example 1 Isolation of μO-conopeptides A657 and F079

[0089] PCR primers designed to amplify “O Superfamily” conotoxin geneswere used in RT-PCR amplification of venom duct cDNA from a variety ofConus species. The primers have the following sequences: Forward Primer:μOCon6 CAGGATCCATGAAACTGACGTGYRTGGTG (SEQ ID NO:22) Reverse Primer:μOCon7 ATCTCGAGCACAGGTATGGATGACTCAGG (SEQ ID NO:23).

[0090] Amplification products in the appropriate size range were clonedand sequenced. A range of “O-Superfamily” gene sequences wereidentified. The novel genes, A657 from C. skinneri, F079, F080 and G28from C. tessulatus, F763 from C. atlanticus, F008 from C. arenatus,Tx6.12 and Tx6.13 from C. textile and G18 from C. generalis, wereidentified as μO-conopeptides on the basis of their similarity to theμ-O conopeptides MrVIA and MrVIB. This similarity was much greater thanthe similarity with any of the ω-, κ- or δ-conopeptides that comprisethe “O Superfamily” peptides. The cDNA and amino acid sequence for theA657, F079, Ca6.1, Tx6.12 (portion), Tx6.13 (portion), G28, F763, F080,F008 and G18 propeptides are set forth in Tables 1-10, respectively. Theamino acid sequences of the mature μO-conopeptides are as shown above.The DNA and amino acid sequences for the Ca6.1, Ca6.2, Ep6.3, Nb6.1,Ts6.1, Ts6.5, Tx6.12 and Tx6.13 are shown in Table 11. TABLE 1 +HZ,41DNA Sequence (SEQ ID NO:23) and Protein Sequence (SEQ ID NO:24) of A657atg aaa ctg acg tgt gtg gtg atc gtt gct gtg ctg ttc ttg acc gcc Met LysLeu Thr Cys Val Val Ile Val Ala Val Leu Phe Leu Thr Ala tgg aca ttc gtcatg gct gat gac ccc aga gat gga gcg gag att aga Trp Thr Phe Val Met AlaAsp Asp Pro Arg Asp Gly Ala Glu Ile Arg agc atg gta agg ggg gaa cct ctgtcg aag gca cgt gac gaa atg aac Ser Met Val Arg Gly Glu Pro Leu Ser LysAla Arg Asp Glu Met Asn ccc gaa gcc tct aaa ttg gag aaa agg gcg tgc cgccaa aaa tac gaa Pro Glu Ala Ser Lys Leu Glu Lys Arg Ala Cys Arg Gln LysTyr Glu ttt tgt cta gta ccg atc att gga tac ata tat tgc tgc gct ggc ttaPhe Cys Leu Val Pro Ile Ile Gly Tyr Ile Tye Cys Cys Ala Gly Leu atc tgtggt cct ttc gtc tgc ctt tgatagtgat gtcttctact gccatctgtg Ile Cys Gly ProPhe Val Cys Leu ctacccctgg cttgatcttt gataggcgtt gttgcccttc actggtttatgaaccctctg atcatactct ctggaccctt gggggtccaa catccaaata aagcgacatcccaaaaaaaa aaaaaaaaaa

[0091] TABLE 2 DNA Sequence (SEQ ID NO:25) and Protein Sequence (SEQ IDNO:26) of F079 gga tcc atg aaa ctg acg tgc atg gtg atc gtt gtt gtg ctgttg ttg Gly Ser Met Lys Leu Thr Cys Met Val Ile Val Val Val Leu Leu Leuaac gcc tgg aca ttc gtc tcc ata aat gga aag gcg aat cgt ttt tgg Asn AlaTrp Thr Phe Val Ser Ile Asn Gly Lys Ala Asn Arg Phe Trp aag gca cgt gacgaa atg aag gac tcc gaa gtt tct gaa ttg gag aaa Lys Ala Arg Asp Glu MetLys Asp Ser Glu Val Ser Glu Leu Glu Lys agg agg aaa ccg acc tgc ctg aagcag gac aag ttt tgc ata ata ccg Arg Arg Lys Pro Thr Cys Leu Lys Gln AspLys Phe Cys Ile Ile Pro ctc att gga acc ctt tat tgc tgc agt ggg tta atctgt ggg ttt ttt Leu Ile Gly Thr Leu Tyr Cys Cys Ser Gly Leu Ile Cys GlyPhe Phe gtc tgc gtc cca aag ccg ttc tgatgtcttc tactgccatc tgtgctaccc ValCys Val Pro Lys Pro Phe ctggcttgat ctttgattgg cgtgtgccct tcactggttatgaacccctc tgatcctact gtctggacgc ctcgggcgtc caacgtccaa ataaagcgacatcccaataa aaaaaaaaaa aaaaaaa

[0092] TABLE 3 DNA Sequence (SEQ ID NO:27) and Protein Sequence (SEQ IDNO:28) of Ca6.1 atg aaa ctg acg tgc gtg atg atc gtt gct gtg ctg ttc ttgacc gcc Met Lys Leu Thr Cys Val Met Ile Val Ala Val Leu Phe Leu Thr Alatgg aca ttc gtc acg gct gat gac tcc att aat gca ctg gag gat ctt Trp ThrPhe Val Thr Ala Asp Asp Ser Ile Asn Ala Leu Glu Asp Leu ttt tcg aag gcacgt gac gaa atg gaa aac ggc gaa gct tct aca ttg Phe Ser Lys Ala Arg AspGlu Met Clu Asn Gly Glu Ala Ser Thr Leu aac gag aga gac tgc gaa gca gatggt gca ttt tgt ggt atc cca att Asn Glu Arg Asp Cys Glu Ala Asp Gly AlaPhe Cys Gly Ile Pro Ile gtg aag aac tgg atg tgc tgc agt aac ttg tgt attttt gcc tgc gta Val Lys Asn Trp Met Cys Cys Ser Asn Leu Cys Ile Phe AlaCys Val ccc gag tat taagactgcc gtgatgtctt ctcctcccct c Pro Glu Tyr

[0093] TABLE 4 DNA Sequence (SEQ ID NO:29) and Protein Sequence (SEQ IDNO:30) of Tx6.12 a ttg gag aaa agg gat tgc cac gaa agg tgg gat tgg tgtcca gca tca   Leu Glu Lys Arg Asp Cys His Glu Arg Trp Asp Trp Cys ProAla Ser atc ctt gga gtg ata tat tgc tgc gag gga tta att tgt ttt att gccIle Leu Gly Val Ile Tyr Cys Cys Glu Gly Leu Ile Cys Phe Ile Ala ttc tgcatt tgatagtgat gtcttctcct cccctc Phe Cys Ile

[0094] TABLE 5 DNA Sequence (SEQ ID NO:31) and Protein Sequence (SEQ IDNO:32) of Tx6.13 a ttg gag aaa agg gat tgc caa gag aaa tgg gag ttt tgtata gta ccg   Leu Glu Lys Arg Asp Cys Gln Glu Lys Trp Glu Phe Cys IleVal Pro atc ctt gga ttt gta tat tgc tgc cct ggc tta atc tgt ggc cct tttIle Leu Gly Phe Val Tyr Cys Cys Pro Gly Leu Ile Cys Gly Pro Phe gtc tgcgtt gat atc tgatgtcttc tcctcccatc Val Cys Val Asp Ile

[0095] TABLE 6 DNA Sequence (SEQ ID NO:33) and Protein Sequence (SEQ IDNO:34) of G28 ggatcc atg aaa ctg acg tgt gtg gtg atc gtt gtt gtg ctg ttgttg        Met Lys Leu Thr Cys Val Val Ile Val Val Val Leu Leu Leu aacgcc tgg aca ttc gtc tcc ata aat gga aag gcg aat cct ttt tgg Asn Ala TrpThr Phe Val Ser Ile Asn Gly Lys Ala Asn Pro Phe Trp aag gca cgt gac gaaatg aag gac tcc gaa gtt tct gag ttg gag aaa Lys Ala Arg Asp Glu Met LysAsp Ser Glu Val Ser Glu Leu Glu Lys agg agg aaa ccg acc tgc gtg tcg tataac gtg ttt tgc gga gta ccg Arg Arg Lys Pro Thr Cys Val Ser Tyr Asn ValPhe Cys Gly Val Pro ctc gtt gga acc tac ctt tgc tgc agt ggc tta gtc tgtctc gta gtc Leu Val Gly Thr Tyr Leu Cys Cys Ser Gly Leu Val Cys Leu ValVal tgc atc tagtactgat gtcttctact cccatctgtg ctacccctcg ag Cys Ile

[0096] TABLE 7 DNA Sequence (SEQ ID NO:35) and Protein Sequence (SEQ IDNO:36) of F763 ggatcc atg aaa ctg acg tgc gtg gtg atc gtt gct gtg ctgttc ttg        Met Lys Leu Thr Cys Val Val Ile Val Ala Val Leu Phe Leuacc gcc tgg aca ttc gtc acg gct gat gac tcc ata aat ggg ttg gag Thr AlaTrp Thr Phe Val Thr Ala Asp Asp Ser Ile Asn Gly Leu Glu aat ctt ttt ccgaag gca cgt cac gaa atg agg aaa ccc gaa gcc tct Asn Leu Phe Pro Lys AlaArg His Glu Met Arg Lys Pro Glu Ala Ser aga tcg aga ggg agg tgc cgt cctcgt ggt atg ttc tgt ggc ttt ccg Arg Ser Arg Gly Arg Cys Arg Pro Arg GlyMet Phe Cys Gly Phe Pro aaa cct gga cca tac tgc tgc aat ggc tgg tgc tttttc gtc tgc atc Lys Pro Gly Pro Tyr Cys Cys Asn Gly Trp Cys Phe Phe ValCys Ile taaaactgcc gtgatgtgtt ctactcccat ctgtgctacc cctcgag

[0097] TABLE 8 DNA Sequence (SEQ ID NO:37) and Protein Sequence (SEQ IDNO:38) of F080 ggatcc atg aaa ctg acg tgc gtg gtg gtc gtt gct gtg ctgttc ttg        Met Lys Leu Thr Cys Val Val Val Val Ala Val Leu Phe Leuaac gcc tgg aca ttc gcc acg gct gtt gac tcc aaa cat gca ctg gcg Asn AlaTrp Thr Phe Ala Thr Ala Val Asp Ser Lys His Ala Leu Ala aaa ctt ttt atgaag gca cgt gac gaa atg tat aac ccc gat gcc act Lys Leu Phe Met Lys AlaArg Asp Glu Met Tyr Asn Pro Asp Ala Thr aaa ttg gac gat aag aga tgg tgcgct tta gat ggt gaa ctt tgt atc Lys Leu Asp Asp Lys Arg Trp Cys Ala LeuAsp Gly Glu Leu Cys Ile ata ccg gtc att ggg tcc ata ttt tgc tgc cat ggcata tgt atg atc Ile Pro Val Ile Gly Ser Ile Phe Cys Cys His Gly Ile CysMet Ile tac tgc gtc tagttgaact gccgtgatgt cttctactcc cctctgtgct Tyr CysVal acccctggtt tgatctttga ttgccctgtg cccttcactg attatgaatc cctctgatcctactctctga agacctcttg gggtccaaca tccaaataaa gcgacatccc aaaaaaaaaaaaaaaaaaaa

[0098] TABLE 9 DNA Sequence (SEQ ID NO:39) and Protein Sequence (SEQ IDNO:40) of F008 ggatcc atg aaa ctg acg tgt gtg gtg atc gtt gct gtg ctgttc ttg        Met Lys Leu Thr Cys Val Val Ile Val Ala Val Leu Phe Leuacc gcc tgg aca ttc gtc acg gct gac tcc ata cgt gca ctg gag gat Thr AlaTrp Thr Phe Val Thr Ala Asp Ser Ile Arg Ala Leu Glu Asp ttt ttt gcg aaggca cgt gac gaa atg gaa aac agc gga gct tct cca Phe Phe Ala Lys Ala ArgAsp Glu Met Glu Asn Ser Gly Ala Ser Pro ttg aac gag aga gac tgc cga cctgta ggt caa tat tgt ggc ata ccg Leu Asn Glu Arg Asp Cys Arg Pro Val GlyGln Tyr Cys Gly Ile Pro tat aag cac aac tgg cga tgc tgc agt cag ctt tgtgca att atc tgt Tyr Lys His Asn Trp Arg Cys Cys Ser Gln Leu Cys Ala IleIle Cys gtt tcc taacccctct gatcctactc tctgaagacc tccgggattc aacatccaaaVal Ser taaagcgaca tcccgatnaa aaaaaangaa aaaaaaaaaa aaaa

[0099] TABLE 10 DNA Sequence (SEQ ID NO:41) and Protein Sequence (SEQ IDNO:42) of G18 ggatcc atg aaa ctg acg tgt gtg gtg atc gtt gct gtg cta ttcttg        Met Lys Leu Thr Cys Val Val Ile Val Ala Val Leu Phe Leu accgcc tgg aca ttc gtc acg gct gat gac acc aga tat aaa ctg gag Thr Ala TrpThr Phe Val Thr Ala Asp Asp Thr Arg Tyr Lys Leu Glu aat cct ttt ctg aaggca cgc aac gaa ctg cag aaa cac gaa gcc tct Asn Pro Phe Leu Lys Ala ArgAsn Glu Leu Gln Lys His Glu Ala Ser caa ctg aac gag aga ggc tgc ctt gaccca ggt tac ttc tgt ggg acg Gln Leu Asn Glu Arg Gly Cys Leu Asp Pro GlyTyr Phe Cys Gly Thr ccg ttt ctt gga gca tac tgc tgc ggt ggc att tgc cttatt gtc tgc Pro Phe Leu Gly Ala Tyr Cys Cys Gly Gly Ile Cys Leu Ile ValCys ata gaa acg taaaggcttg atgtcttcta ctcccatctg tgctacccct cgag Ile GluThr

[0100] TABLE 11 DNA and Amino Acid Sequences of Mu—O ConopeptidesName:      Ca6.1 Species:   caracteristicus Isolated:  No Cloned:    YesDNA Sequence:ATGAAACTGACGTGCGTGATGATCGTTGCTGTGCTGTTCTTGACCGCCTGGACATTCGT (SEQ IDNO:43) CACGGCTGATGACTCCATTAATGCACTGGAGGATCTTTTTTCGAAGGCACGTGACGAAATGGAAAACGGCGAAGCTTCTACATTGAACGAGAGAGACTGCGAAGCAGATGGTGCATTTTGTGGTATCCCAATTGTGAAGAACTGGATGTGCTGCAGTAACTTGTGTATTTTTGCCTGCGTACCCGAGTATTAAGACTGCCGTGATGTCTTCTCCTCCCCTC Translation:MKLTCVMIVAVLFLTAWTFVTADDSINALEDLFSKARDEMENGEASTLNERDCEADGAFC (SEQ IDNO:44) GIPIVKNWMCCSNLCIFACVPEY Toxin Sequence:Asp-Cys-Xaal-Ala-Asp-Gly-Ala-Phe-Cys-GlY-Ile-Xaa3-Ile-Val-Lys-Asn-Xaa4-Met-Cys-Cys-Ser-(SEQ ID NO:45)Asn-Leu-Cys-Ile-Phe-Ala-Cys-Val-Xaa3-Xaa1-Xaa5-{circumflex over ( )}Name:      Nb6.1 Species:   nobilis Isolated:  No Cloned:    Yes DNASequence: ATGAAACTGACGTGTGTGGTGATCGTTGCTGTGCTGTTCTTGACCGCCTGGACATTCGT(SEQ ID NO:46)CATGGCTGATGACCCCAGAGATGGAGCGGAGATTAGAAGCATGGTAAGGGGGGAACCTCTGTCGAAGGCACGTGACGAAATGAACCCCGAAGCCTCTAAATTGGAGAAAAGGGCGTGCCGCCAAAAATACGAATTTTGTCTAGTACCGATCATTGGATACATATATTGCTGCGCTGGCTTAATCTGTGGTCCTTTCGTCTGCCTTTGATAGTGATGTCTTCTACTGCCATCTGTGCTACCCCTGGCTTGATCTTTGATAGGCGTTGTTGCCCTTCACTGGTTTATGAACCCTCTGATCATACTCTCTGGACCCTTGGGGGTCCAACATCCAAATAAAGCGACATCCCAAAAAA AAAAAAAAAAAATranslation:MKLTCVVIVAVLFLTAWTFVMADDPRDGAEIRSMVRGEPLSKARDEMNPEASKLEKRACR (SEQ IDNO:47) QKYEFCLVPIIGYIYCCAGLICGPFVCL Toxin Sequence:Ala-Cys-Arg-Gln-Lys-Xaa5-Xaa1-Phe-Cys-Leu-Val-Xaa3-Ile-Ile-Gly-Xaa5-Ile-Xaa5-Cys-Cys-(SEQ ID NO:48) Ala-Gly-Leu-Ile-Cys-Gly-Xaa3-Phe-Val-Cys-Leu-{circumflexover ( )} Name:      Tx6.12 Species:   textile Isolated:  NoCloned:    Yes DNA Sequence:ATTGGAGAAAAGGGATTGCCACGAAAGGTGGGATTGGTGTCCAGCATCAATCCTTGGA (SEQ IDNO:49) GTGATATATTGCTGCGAGGGATTAATTTGTTTTATTGCCTTCTGCATTTGATAGTGATGTCTTCTCCTCCCCTC Translation: LEKRDCHERWDWCPASILGVIYCCEGLICFIAFCI (SEQ IDNO:50) Toxin Sequence:Asp-Cys-His-Xaa1-Arg-Xaa4-Asp-Xaa4-Cys-Xaa3-Ala-Ser-Ile-Leu-Gly-Val-Ile-Xaa5-Cys-Cys-(SEQ ID NO:51) Xaa1-Gly-Leu-Ile-Cys-Phe-Ile-Ala-Phe-Cys-Ile-{circumflexover ( )} Name:      Tx6.13 Species:   textile Isolated:  NoCloned:    Yes DNA Sequence:ATTGGAGAAAAGGGATTGCCAAGAGAAATGGGAGTTTTGTATAGTACCGATCCTTGGA (SEQ IDNO:52) TTTGTATATTGCTGCCCTGGCTTAATCTGTGGCCCTTTTGTCTGCGTTGATATCTGATGTCTTCTCCTCCCATC Translation: LEKRDCQEKWEFCIVPILGFVYCCPGLICGPFVCVDI (SEQ IDNO :53) Toxin Sequence:Asp-Cys-Gln-Xaa1-Lys-Xaa4-Xaa1-Phe-Cys-Ile-Val-Xaa3-Ile-Leu-Gly-Phe-Val-Xaa5-Cys-Cys-(SEQ ID NO:54)Xaa3-Gly-Leu-Ile-Cys-Gly-Xaa3-Phe-Val-Cys-Val-Asp-Ile-{circumflex over( )} Name:      Ts6.1 Species:   tessulatus Isolated:  No Cloned:    YesDNA Sequence:GGATCCATGAAACTGACGTGCATGGTGATCGTTGTTGTGCTGTTGTTGAACGCCTGGAC (SEQ IDNO:55) ATTCGTCTCCATAAATGGAAAGGCGAATCGTTTTTGGAAGGCACGTGACGAAATGAAGGACTCCGAAGTTTCTGAATTGGAGAAAAGGAGGAAACCGACCTGCCTGAAGCAGGACAAGTTTTGCATAATACCGCTCATTGGAACCCTTTATTGCTGCAGTGGGTTAATCTGTGGGTTTTTTGTCTGCGTCCCAAAGCCGTTCTGATGTCTTCTACTGCCATCTGTGCTACCCTGGCTTGATCTTTGATTGGCGTGTGCCCTTCACTGGTTATGAACCCCTCTGATCCTACTGTCTGGACGCCTCGGGCGTCCAACGTCCAAATAAAGCGACATCCCAATAAAAAAAAAAAAA AAAAAATranslation:MKLTCMVIVVVLLLNAWTFVSINGKANRFWKARDEMKDSEVSELEKRRKPTCLKQDKFCI (SEQ IDNO:56) IPLIGTLYCCSGLICGFFVCVPKPF Toxin Sequence:Xaa3-Thr-Cys-Leu-Lys-Gln-Asp-Lys-Phe-Cys-Ile-Ile-Xaa3-Leu-Ile-Gly-Thr-Leu-Xaa5-Cys-Cys-(SEQ ID NO:57)Ser-Gly-Leu-Ile-Cys-Gly-Phe-Phe-Val-Cys-Val-Xaa3-Lys-Xaa3-Phe-{circumflexover ( )} Name:      Ts6.5 Species:   tessulatus Isolated:  NoCloned:    Yes DNA Sequence:GGATCCATGAAACTGACGTGTGTGGTGATCGTTGTTGTGCTGTTGTTGAACGCCTGGAC (SEQ IDNO:58) ATTCGTCTCCATAAATGGAAAGGCGAATCCTTTTTGGAAGGCACGTGACGAAATGAAGGACTCCGAAGTTTCTGAGTTGGAGAAAAGGAGGAAACCGACCTGCGTGTCGTATAACGTGTTTTGCGGAGTACCGCTCGTTGGAACCTACCTTTGCTGCAGTGGCTTAGTCTGTCTCGTAGTCTGCATCTAGTACTGATGTCTTCTACTCCCATCTGTGCTACCCCTCGAG Translation:MKLTCVVIVVVLLLNAWTFVSINGKANPFWKARDEMKDSEVSELEKRRKPTCVSYNVFCG (SEQ IDNO:59) VPLVGTYLCCSGLVCLVVCI Toxin Sequence:Xaa3-Thr-Cys-Val-Ser-Xaa5-Asn-Val-Phe-Cys-Gly-Val-Xaa3-Leu-Val-Gly-Thr-Xaa5-Leu-Cys-(SEQ ID NO:60) Cys-Ser-Gly-Leu-Val-Cys-Leu-Val-Val-Cys-Ile-{circumflexover ( )} Name:      Ca6.2 Species:   caracteristicus Isolated:  NoCloned:    Yes DNA Sequence:GGATCCATGAAACTGACGTGCATGGTGATCGTTGCTGTGCTGTTCTTGACCGCCTGGAC (SEQ IDNO:61) ATTCGTCACGGCTGATGACTCCATTAATGCACTGGAGGATCTTTTTTCGAAGGCACGCGACGAAATGGAAAACGGCGAAGCTTCTACATTGAACGAGAGAGACTGCGAAGCAGATGGTGCATTTTGTGGTATCCCAACTGTGAAGAACTGGATGTGCTGCAGTAACTTGTGTATTTTTGCCTGCGTACCCGAGTATTAAGACTGCCGTGATGTCTTCTGCTCCCCTCTGTGCTACCTGGCTTGATCTTTGATTGGCGCGTGCCCTTCACTGGTTATGAACCCCTCTGATCCTACTC TCTranslation:MKLTCMVIVAVLFLTAWTFVTADDSINALEDLFSKARDEMENGEASTLNERDCEADGAFC (SEQ IDNO:62) GIPTVKNWMCCSNLCIFACVPEY Toxin Sequence:Asp-Cys-Xaa1-Ala-Asp-Gly-Ala-Phe-Cys-Gly-Ile-Xaa3-Thr-Val-Lys-Asn-Xaa4-Met-Cys-Cys-Ser-(SEQ ID NO:63)Asn-Leu-Cys-Ile-Phe-Ala-Cys-Val-Xaa3-Xaa1-Xaa5-{circumflex over ( )}Name:      Ep6.3 Species:   episcopatus Isolated:  No Cloned:    Yes DNASequence: GGATCCATGAAACTGACGTGTGTGGTGATCATTGCTGTGCTGTTCTTGACCGCCTGGAC(SEQ ID NO:64)ATTCGTCATGGCTGATGACTCCAACAATGGACTGGCGAATCATTTTTCGAAATCACGTGACGAAATGGAGGACCCCGAAGCTTCTAAATTGGAGAAAAGAAGGGATTGCCAAGAAGAATGGGAATTTTGTATAGTACCGATCCTTGGATTCGTATATTGCTGCCCTGGCTTAATCTGTGGTCCTTTCGTCTGCGTTTAATACTGATGTCTTCTACTCCCATCTGTGCTACACCTGGCTTGATCTTTGATAGGCGTGTGCCCTTCACTGGTTATAAACCCCTCTGATCCTACTCTCTGGACGCCTCGGGGGCCCAACATCCAAATAAAGCAACATCCCAATGAANAAAAAA Translation:MKLTCVVIIAVLFTAWTFVMADDSNNGLANHFSKSRDEMEDPEASKLEKRRDCQEEWEF (SEQ IDNO:65) CIVPILGFVYCCPGLICGPFVCV Toxin Sequence:Asp-Cys-Gln-Xaa1-Xaa1-Xaa4-Xaa1-Phe-Cys-Ile-Val-Xaa3-Ile-Leu-Gly-Phe-Val-Xaa5-Cys-Cys-(SEQ ID NO:66) Xaa3-Gly-Leu-Ile-Cys-Gly-Xaa3-Phe-Val-Cys-Val-{circumflexover ( )}

Example 2 Effect of Intrathecal Administration of MrV,IB

[0101] Male C57 black mice (20-25g) were obtained from Charles RiverLaboratories. These mice and the animals used in the other examples werehoused in a temperature controlled (23°±3° C.) room with a 12 hourlight-dark cycle with free access to food and water. All animals wereeuthanized in accordance with Public Health Service policies on thehumane care of laboratory animals.

[0102] Intrathecal (it) drug injections were performed as described(Hylden and Wilcox, 1980). MrVIB (10 nmol) or vehicle was administeredin a volume of 5 μl. Duration of hind-limb paralysis was assessed. Thisexperiment revealed that injection of 10 nmols of MrVIB into theintrathecal space of C57 black mice produced a long-lasting paralysis(>20 hrs) of the animal. The injection initially produced a paralysis ofthe hind-limbs, but over the following 30 minutes resolved intoparalysis of the entire animal. Despite the long duration of anesthesia,the animals in this experiment recovered fully. Similar results wereobtained with MrVIA. Similar results are also obtained with A657, F079,Ca6.1, Tx6.12, Tx6.13, G28, F763 and F080.

Example 3 Effect of MrVIB as a Local Anesthetic

[0103] Male Hartley guinea pigs (retired breeders) were obtained formCharles River Laboratories. The local anesthetic test was performedessentially as described (Bulbring and Wajda, 1945). On the day prior totest day, a patch on the back of the guinea pig was denuded of hair,first by shaving with electric clippers and subsequently with depilatorycream (Nair®). Depilatory cream was applied for five minutes and removedwith a warm washcloth. The guinea pigs were dried and returned to theircages. On the following day, intradermal injections (0.1 ml vols) oflidocaine, bupivacaine, MrVIB or vehicle (0.5% cyclodextran) were madeinto the denuded patch. The injection produced a raised wheal on thesurface of the skin which was circled with a felt-tipped pen. Typically,four injections were made on the back of each guinea pig. In some cases,guinea pigs were reused following at least one week of recovery andinjecting into an unused portion of the skin.

[0104] The stimulus consisted of mild pin pricks (not hard enough tobreak the skin) with a 26G needle. The response is a localized skintwitch caused by contraction of cutaneous muscles. A unit test consistedof six uniform pin pricks, 3-5 seconds apart, within the injected area.Unit scores ranged from 0 (complete anesthesia) to 6 (no anesthesia).For potency experiments, the unit test was repeated at each site at fiveminute intervals for 30 minutes, and unit test scores summed (with 36representing no anesthesia to 0 representing complete anesthesia. Forduration experiments, unit tests were performed as described over thecourse of several hours to days.

[0105] MrVIB produced a potent (FIG. 1) and long lasting (FIG. 2) localanesthetic effect in the intracutaneous wheat test in the guinea pig.The ED₅₀'s for this response (≈100 pmol) was at least two orders ofmagnitude greater than the ED₅₀'s for lidocaine and bupivacaine.Moreover, the duration of roughly equieffective doses of MrVIB (roughly24 and 48 hours for full recovery following 1 and 10 nmol, respectively)was much longer than that of lidocaine and bupivacaine (≈30 and 90minutes for fall recovery, respectively). As expected, bupivacaine had aslightly longer duration than lidocaine, consistent with clinicalobservations. It was seen during the experiment that the intracutaneouswheal consistently turned red several hours following injection ofMrVIB, possibly suggesting an antigenic action. Similar results areobtained with MrVIA, A657, F079, Ca6.1, Tx6.12, Tx6.13, G28, F763 andF080.

[0106] While the invention has been disclosed in this patent applicationby reference to the details of preferred embodiments of the invention,it is to be understood that the disclosure is intended in anillustrative rather than in a limiting sense, as it is contemplated thatmodifications will readily occur to those skilled in the art, within thespirit of the invention and the scope of the appended claims.

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0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 66 <210> SEQ ID NO 1<211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Generic peptide <221> NAME/KEY:PEPTIDE <222> LOCATION: (1)..(2) <223> OTHER INFORMATION: Xaa at residue1 is des-Xaa, Pro, Hyp, Arg, Lys, ornithine, homo-Lys, homoarginine,nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N′′-trimethyl-Lys or anysynthetic basic amino acid; Xaa at residue 2 is des-Xaa, Ala, Gly, Asp,Glu, Gla, any <221> NAME/KEY: PEPTIDE <222> LOCATION: (2)..(4) <223>OTHER INFORMATION: synthetic acidic amino acid, Thr, Ser, g-Thr, g-Ser,Trp (D or L), neo-Trp or halo-Trp (D or L) or Xaa may be pyro-Glu if Xaaat residue 1 is des-Xaa; Xaa at residue 4 is Arg, Lys, ornithine,homo-Lys, homoarginine, nor-Lys, <221> NAME/KEY: PEPTIDE <222> LOCATION:(4)..(4) <223> OTHER INFORMATION: N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N′′-trimethyl-Lys, any synthetic basic amino acid, Ser, Thr, g-Ser,g-Thr, Ala, an aliphatic amino acids bearing linear or branchedsaturated hydrocarbon chains such as Leu (D or L), Ile an <221>NAME/KEY: PEPTIDE <222> LOCATION: (4)..(5) <223> OTHER INFORMATION: andVal or non-natural derivatives of the aliphatic amino acid, H is, Glu,Gln, Gla, Asp, Asn or any synthetic acidic amino acid; X aa at residue 5is Glu, Gla, Gln, Asp, Asn, any synthetic acidic amino acid, Lys, Arg,ornithine <221> NAME/KEY: PEPTIDE <222> LOCATION: (5)..(5) <223> OTHERINFORMATION: homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N′′- trimethyl-Lys, any synthetic basic aminoacid, Ala, an aliphatic amino acids bearing linear or branched saturatedhydrocarbon chains such as Leu (D or L), <221> NAME/KEY: PEPTIDE <222>LOCATION: (5)..(6) <223> OTHER INFORMATION: Ile and Val or non-naturalderivatives of the aliphatic amino acid, Ser, Thr, Pro, Hyp, g-Ser,g-Thr, g-Hyp or any synthetic hydroxylated amino acid; Xaa at residue 6is Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, <221> NAME/KEY:PEPTIDE <222> LOCATION: (6)..(6) <223> OTHER INFORMATION: N-methyl-Lys,N,N′-dimethyl-Lys, N,N′, N′′-trimethyl-Lys, any synthetic basic aminoacid, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, an aliphatic amino acids bearinglinear or <221> NAME/KEY: PEPTIDE <222> LOCATION: (6)..(7) <223> OTHERINFORMATION: or branched saturated hydrocarbon chains such as Leu (D orL), Ile and Val or non-natural derivatives of the aliphatic amino acid,Glu, Gla, Gln, Asp, Asn, any synthetic acidic amino acid, Pro or Hyp;Xaa at residue 7 is Trp (D or L), <221> NAME/KEY: PEPTIDE <222>LOCATION: (7)..(8) <223> OTHER INFORMATION: neo-Trp, halo-Trp (D or L),Gly, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Glu, Gla, Gln, Asp, Asn, anysynthetic acidic amino acid; X aa at residue 8 is Glu, Gla, Gln, Asp,Asn, <221> NAME/KEY: PEPTIDE <222> LOCATION: (8)..(8) <223> OTHERINFORMATION: any synthetic acidic amino acid, Met, norleucine (Nle),Ala, an a liphatic amino acids bearing linear or branched saturatedhydrocarbon chains such as Leu (D or L), Ile and Val or non-naturalderivatives of the aliphatic amino acid, Tyr, <221> NAME/KEY: PEPTIDE<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: meta-Tyr, ortho-Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys,N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N′′-trimethyl-Lys or any syntheti<221> NAME/KEY: PEPTIDE <222> LOCATION: (8)..(9) <223> OTHERINFORMATION: basic amino acid; Xaa at residue 9 is Leu, Phe, Tyr,meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-pho spho-Tyr, nitro-Tyr, Trp (D or L), neo-Trp, halo-Trp (D or L) orany synthetic aromatic amino acid; <221> NAME/KEY: PEPTIDE <222>LOCATION: (11)..(11) <223> OTHER INFORMATION: Xaa at residue 11 is Pro,Hyp, Gly, an aliphatic amino acids bearing linear or branched saturatedhydrocarbon chains such as Leu (D or L), Ile and Val or non-naturalderivatives of the aliphatic amino acid; <221> NAME/KEY: PEPTIDE <222>LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa at residue 12 is Thr,Ser, g-Thr, g-Ser, Ala, an aliphatic amino acids bearing linear orbranched saturated hydrocarbon chains such as Leu (D or L), Ile and Valor non-natural derivatives of the aliphatic amino acid, Phe, Tyr <221>NAME/KEY: PEPTIDE <222> LOCATION: (12)..(13) <223> OTHER INFORMATION:meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr, Trp (D or L), neo-Trp, halo-Trp (D or L) orany synthetic aromatic amino acid; Xaa at residue 13 is Pro, Hyp, Ser,Thr, g-Hyp, <221> NAME/KEY: PEPTIDE <222> LOCATION: (13)..(14) <223>OTHER INFORMATION: g-Ser, g-Thr or any hydroxylated amino acid; Xaa atresidue 14 is an aliphatic amino acids bearing linear or branchedsaturated hydrocarbon chains such as Leu (D or L), Ile and Val ornon-natural derivatives of the aliphatic amino acid, <221> NAME/KEY:PEPTIDE <222> LOCATION: (14)..(14) <223> OTHER INFORMATION: Phe, Tyr,meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr, Lys, Arg, ornithine, homo-Lys, homoarginine,nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N′′-trimethyl-Lys or anysyntheti <221> NAME/KEY: PEPTIDE <222> LOCATION: (14)..(15) <223> OTHERINFORMATION: basic amino acid; Xaa at residue 15 is Pro, Hyp, analiphatic amino acids bearing linear or branched saturated hydrocarbonchains such as Leu (D or L), Ile and Val or non-natural derivatives ofthe aliphatic amino acid, Lys, Arg, <221> NAME/KEY: PEPTIDE <222>LOCATION: (15)..(16) <223> OTHER INFORMATION: ornithine, homo-Lys,homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys,N,N′,N′′-trimethyl-Lys or any synthetic basic amino acid; Xaa at residue16 is Gly, His, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys,<221> NAME/KEY: PEPTIDE <222> LOCATION: (16)..(17) <223> OTHERINFORMATION: N-methyl-Lys, N,N′-dimethyl-Lys, N,N′, N′′-trimethyl-Lys orany synthetic basic amino acid; Xaa at residue 17 is des-Xaa15, Ser,Thr, g-Ser, g-Thr, Val, Asn, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr,mono-halo-Tyr, di-halo-Tyr, <221> NAME/KEY: PEPTIDE <222> LOCATION:(17)..(18) <223> OTHER INFORMATION: O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr, Trp (D or L), neo-Trp, halo-Trp (D or L) or any syntheticaromatic amino acid; Xaa at residue 18 is Met, Nle, an aliphatic aminoacids bearing linear or branched saturated hydrocarbon chain <221>NAME/KEY: PEPTIDE <222> LOCATION: (18)..(18) <223> OTHER INFORMATION:such as Leu (D or L), Ile and Val or non-natural derivatives of thealiphatic amino acid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr,mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Trp(D or L), neo-Trp, <221> NAME/KEY: PEPTIDE <222> LOCATION: (18)..(19)<223> OTHER INFORMATION: halo-Trp (D or L), any synthetic aromatic aminoacid, Arg, Lys, ornithine, homo-Lys, homoarginine, nor-Lys,N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N′′-trimethyl-Lys or any syntheticbasic amino acid; Xaa at residue 19 is Pro, Hyp, Ser, <221> NAME/KEY:PEPTIDE <222> LOCATION: (19)..(19) <223> OTHER INFORMATION: Thr, g-Hyp,g-Ser, g-Thr, any hydroxylated amino acid, Ala, Met, Leu, Glu, Gla, Gln,Asp, Asn, any synthetic acidic amino acid, Tyr, meta-Tyr, ortho-Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr, His or Gly; <221> NAME/KEY: PEPTIDE <222> LOCATION:(22)..(24) <223> OTHER INFORMATION: Xaa at residue 22 is Gly, Ala, Ser,Thr, Pro, Hyp, g-Ser, g-Thr, g-Hyp, Glu, Asn or Gln; Xaa at residue 23is Leu, Gly, Asn, Trp (D or L), neo-Trp or halo-Trp (D or L); Xaa atresidue 24 is des-Xaa, Leu or Trp (D or L), neo-Trp or halo-Trp (D orL); <221> NAME/KEY: PEPTIDE <222> LOCATION: (25)..(27) <223> OTHERINFORMATION: Xaa at residue 25 is des-Xaa or an aliphatic amino acidsbearing linear or branched saturated hydrocarbon chains such as Leu (Dor L), Ile and Val or non-natural derivatives of the aliphatic aminoacid; Xaa at residue 27 is des-Xaa, Gly, <221> NAME/KEY: PEPTIDE <222>LOCATION: (27)..(28) <223> OTHER INFORMATION: Met, Nle, Phe, Tyr,meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr, Trp (D or L), neo-Trp, halo-Trp (D or L) orany synthetic aromatic amino acid; Xaa at residue 28 is des-Xaa, Pro,<221> NAME/KEY: PEPTIDE <222> LOCATION: (28)..(28) <223> OTHERINFORMATION: Hyp, Ala, an aliphatic amino acids bearing linear orbranched saturated hydrocarbon chains such as Leu? (D or L), Ile and Valor non-natural derivatives of the aliphatic amino acid, Phe, Tyr,meta-Tyr, ortho-Tyr, nor-Tyr, <221> NAME/KEY: PEPTIDE <222> LOCATION:(28)..(29) <223> OTHER INFORMATION: mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Trp (D or L), neo-Trp, halo-Trp(D or L) or any synthetic aromatic amino acid; Xaa at residue 29 is Ala,an aliphatic amino acid bearing linear or branched <221> NAME/KEY:PEPTIDE <222> LOCATION: (29)..(29) <223> OTHER INFORMATION: saturatedhydrocarbon chains such as Leu (D or L), Ile and Val or non-naturalderivatives of the aliphatic amino acid, Phe, Tyr, meta-Tyr, ortho-Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr <221> NAME/KEY: PEPTIDE <222> LOCATION: (29)..(30) <223> OTHERINFORMATION: Trp (D or L), neo-Trp, halo-Trp (D or L) or any syntheticaromatic amino acid; Xaa at residue 30 is Ala, an aliphatic amino acidbearing linear or branched saturated hydrocarbon chains such as Leu (Dor L), Ile and Val or <221> NAME/KEY: PEPTIDE <222> LOCATION: (30)..(32)<223> OTHER INFORMATION: non-natural derivatives of the aliphatic aminoacid, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or Phe; Xaa at residue 32 is analiphatic amino acids bearing linear or branched <221> NAME/KEY: PEPTIDE<222> LOCATION: (32)..(33) <223> OTHER INFORMATION: saturatedhydrocarbon chains such as Leu (D or L), Ile and Val or non-naturalderivatives of the aliphatic amino acid; Xaa at resi ude 33 is des-Xaa,Asp, Glu, Gla, Pro, Hyp, Ser, Thr, g-Hyp, g-Se r, g-Ser or any synthetichydroxylated amino acid <221> NAME/KEY: PEPTIDE <222> LOCATION:(34)..(34) <223> OTHER INFORMATION: Xaa at residue 34 is des-Xaa, Glu,Gla, Gln, Asp, Asn, any synthetic acidic amino acid, Lys, Arg,ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N′′-trimethyl-Lys, any synthetic basic aminoacid, <221> NAME/KEY: PEPTIDE <222> LOCATION: (34)..(36) <223> OTHERINFORMATION: Ile, Ser, Thr, g-Ser or g-Thr; Xaa at residue 35 isdes-Xaa, Pro, Hyp, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; Xaa at residue 36is des-Xaa or Ph <400> SEQUENCE: 1 Xaa Xaa Cys Xaa Xaa Xaa Xaa Xaa XaaCys Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa Cys Cys Xaa Xaa XaaXaa Cys Xaa Xaa Xaa Xaa Cys Xaa 20 25 30 Xaa Xaa Xaa Xaa 35 <210> SEQ IDNO 2 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Conus magus <220>FEATURE: <221> NAME/KEY: PEPTIDE <222> LOCATION: (1)..(31) <223> OTHERINFORMATION: Xaa at residue 3 may be Arg or Ser; Xaa at residues 12, 21and 27 5 may be Pro or hydroxy-Pro; Xaa at residue 14 may be Ile or Leu; Xaa at residue 17 may be Ile or Va <400> SEQUENCE: 2 Ala Cys Xaa LysLys Trp Glu Thr Cys Ile Val Xaa Ile Xaa Gly Phe 1 5 10 15 Xaa Thr CysCys Xaa Gly Leu Ile Cys Gly Xaa Phe Val Cys Val 20 25 30 <210> SEQ ID NO3 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Conus skinneri <220>FEATURE: <221> NAME/KEY: PEPTIDE <222> LOCATION: (1)..(31) <223> OTHERINFORMATION: Xaa at residue 5 is Lys, N-methyl-Lys, N,N-dimethyl-Lys orN,N,N-trimethyl-Lys; Xaa at residue 6, 16 and 18 may be Tyr,mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Ty<221> NAME/KEY: PEPTIDE <222> LOCATION: (1)..(31) <223> OTHERINFORMATION: Xaa at residue 7 may be Glu or gamma-carboxy-Glu; Xaa atresidues 12 and 27 may be Pro or hydroxy-Pro <400> SEQUENCE: 3 Ala CysArg Gln Xaa Xaa Xaa Phe Cys Leu Val Xaa Ile Ile Gly Xaa 1 5 10 15 IleXaa Cys Cys Ala Gly Leu Ile Cys Gly Xaa Phe Val Cys Leu 20 25 30 <210>SEQ ID NO 4 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Conustessulatus <220> FEATURE: <221> NAME/KEY: PEPTIDE <222> LOCATION:(1)..(36) <223> OTHER INFORMATION: Xaa at residue 1 may be Glu orgamma-carboxy-Glu; Xaa at residues 5, 8 and 34 may be Lys, N-methyl-Lys,N,N-dimethyl-Lys or N,N,N-trimethyl-Ly <221> NAME/KEY: PEPTIDE <222>LOCATION: (1)..(36) <223> OTHER INFORMATION: Xaa at residues 1, 33 and35 may be Pro or hydroxy-Pro ; Xaa at residue 19 may be Tyr,mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Ty<400> SEQUENCE: 4 Xaa Thr Cys Leu Xaa Gln Asp Xaa Phe Cys Ile Ile XaaLeu Ile Gly 1 5 10 15 Thr Leu Xaa Cys Cys Ser Gly Leu Ile Cys Gly PhePhe Val Cys Val 20 25 30 Xaa Xaa Xaa Phe 35 <210> SEQ ID NO 5 <211>LENGTH: 32 <212> TYPE: PRT <213> ORGANISM: Conus caracteristicus <220>FEATURE: <221> NAME/KEY: PEPTIDE <222> LOCATION: (1)..(32) <223> OTHERINFORMATION: Xaa at residues 3 and 31 may be Glu or gamma-carboxy-Glu;Xaa at residues 12 and 30 may be Pro or hydroxy-Pro; Xaa at residue 15may be Lys, N-methyl-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Ly <221>NAME/KEY: PEPTIDE <222> LOCATION: (1)..(32) <223> OTHER INFORMATION: Xaaat residue 14 may be Trp or bromo-Trp; Xaa at residue 32 may be Tyr,mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Ty<400> SEQUENCE: 5 Asp Cys Xaa Ala Asp Gly Ala Phe Cys Gly Ile Xaa IleVal Xaa Asn 1 5 10 15 Xaa Met Cys Cys Ser Asn Leu Cys Ile Phe Ala CysVal Xaa Xaa Xaa 20 25 30 <210> SEQ ID NO 6 <211> LENGTH: 31 <212> TYPE:PRT <213> ORGANISM: Conus textile <220> FEATURE: <221> NAME/KEY: PEPTIDE<222> LOCATION: (1)..(31) <223> OTHER INFORMATION: Xaa at residues 4 and21 is Glu or gamma-carboxy-Glu; Xaa at residues 6 and 8 is Trp orhalo-Trp; Xaa at residue 10 is Pro or hydroxy-Pro; Xaa at residue 18 isTyr, mono-halo-Tyr, di-halo-Tyr, <221> NAME/KEY: PEPTIDE <222> LOCATION:(1)..(31) <223> OTHER INFORMATION: O-sulpho-Tyr, O-phospho-Tyr ornitro-Tyr <400> SEQUENCE: 6 Asp Cys His Xaa Arg Xaa Asp Xaa Cys Xaa AlaSer Ile Leu Gly Val 1 5 10 15 Ile Xaa Cys Cys Xaa Gly Leu Ile Cys PheIle Ala Phe Cys Ile 20 25 30 <210> SEQ ID NO 7 <211> LENGTH: 33 <212>TYPE: PRT <213> ORGANISM: Conus textile <220> FEATURE: <221> NAME/KEY:PEPTIDE <222> LOCATION: (1)..(33) <223> OTHER INFORMATION: Xaa atresidues 4 and 7 is Glu or gamma-carboxy-Glu; Xaa at residue 5 isLys,N-methy-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa at residue 6is Trp or halo-Trp; Xaa at residues 12, 21 and 2 <221> NAME/KEY: PEPTIDE<222> LOCATION: (1)..(33) <223> OTHER INFORMATION: is Pro orhydroxy-Pro; Xaa at residue 18 isTyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr or nitro-Ty <400> SEQUENCE: 7 Asp Cys GlnXaa Xaa Xaa Xaa Phe Cys Ile Val Xaa Ile Leu Gly Phe 1 5 10 15 Val XaaCys Cys Xaa Gly Leu Ile Cys Gly Xaa Phe Val Cys Val Asp 20 25 30 Ile<210> SEQ ID NO 8 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Conustessulatus <220> FEATURE: <221> NAME/KEY: PEPTIDE <222> LOCATION:(1)..(31) <223> OTHER INFORMATION: Xaa at residues 1 and 13 is Pro orhydroxy-Pro; Xaa at residues 6 and 18 is Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Ty <400> SEQUENCE: 8Xaa Thr Cys Val Ser Xaa Asn Val Phe Cys Gly Val Xaa Leu Val Gly 1 5 1015 Thr Xaa Leu Cys Cys Ser Gly Leu Val Cys Leu Val Val Cys Ile 20 25 30<210> SEQ ID NO 9 <211> LENGTH: 27 <212> TYPE: PRT <213> ORGANISM: Conusatlanticus <220> FEATURE: <221> NAME/KEY: PEPTIDE <222> LOCATION:(1)..(27) <223> OTHER INFORMATION: Xaa at residues 3, 11, 13 and 15 isPro or hydroxy-Pro; Xaa at residue 12 is Lys, N-methy-Lys,N,N-dimethyl-Lys or N,N,N-trimethy l-Lys; Xaa at residue 16 is Tyr,mono-halo-Tyr, di-halo-Tyr <221> NAME/KEY: PEPTIDE <222> LOCATION:(1)..(27) <223> OTHER INFORMATION: O-sulpho-Tyr, O-phospho-Tyr ornitro-Tyr; Xaa at residue 21 is Trp or halo-Tr <400> SEQUENCE: 9 Cys ArgXaa Arg Gly Met Phe Cys Gly Phe Xaa Xaa Xaa Gly Xaa Xaa 1 5 10 15 CysCys Asn Gly Xaa Cys Phe Phe Val Cys Ile 20 25 <210> SEQ ID NO 10 <211>LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Conus tessulatus <220>FEATURE: <221> NAME/KEY: PEPTIDE <222> LOCATION: (1)..(30) <223> OTHERINFORMATION: Xaa at residue 2 is Trp or halo-Trp; Xaa at resude 8 is Gluor gamma-carboxy-Glu; Xaa 13 is Pro or hydroxy-Pr <400> SEQUENCE: 10 ArgXaa Cys Ala Leu Asp Gly Xaa Leu Cys Ile Ile Xaa Val Ile Gly 1 5 10 15Ser Ile Phe Cys Cys His Gly Ile Cys Met Ile Xaa Cys Val 20 25 30 <210>SEQ ID NO 11 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Conusarenatus <220> FEATURE: <221> NAME/KEY: PEPTIDE <222> LOCATION:(1)..(30) <223> OTHER INFORMATION: Xaa at residues 4 and 12 is Pro orhydroxy-Pro; Xaa at residues 8 and 13 is Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; Xaa at residue 14is Lys, N-methy-Lys <221> NAME/KEY: PEPTIDE <222> LOCATION: (1)..(30)<223> OTHER INFORMATION: N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa atresidue 17 is Trp or halo-Tr <400> SEQUENCE: 11 Asp Cys Arg Xaa Val GlyGln Xaa Cys Gly Ile Xaa Xaa Xaa His Asn 1 5 10 15 Xaa Arg Cys Cys SerGln Leu Cys Ala Ile Ile Cys Val Ser 20 25 30 <210> SEQ ID NO 12 <211>LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Conus generalis <220>FEATURE: <221> NAME/KEY: PEPTIDE <222> LOCATION: (1)..(30) <223> OTHERINFORMATION: Xaa at residues 5 and 12 is Pro or hydroxy-Pro; Xaa atresidues 7 and 17 isTyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr or nitro-Tyr; Xaa at residue 29 is Glu orgamma-carboxy-Glu <400> SEQUENCE: 12 Gly Cys Leu Asp Xaa Gly Xaa Phe CysGly Thr Xaa Phe Leu Gly Ala 1 5 10 15 Xaa Cys Cys Gly Gly Ile Cys LeuIle Val Cys Ile Xaa Thr 20 25 30 <210> SEQ ID NO 13 <211> LENGTH: 32<212> TYPE: PRT <213> ORGANISM: Conus caracteristicus <220> FEATURE:<221> NAME/KEY: PEPTIDE <222> LOCATION: (1)..(32) <223> OTHERINFORMATION: Xaa at residues 3 and 31 may be Glu or gamma-carboxy-Glu;Xaa at residues 12 and 30 may be Pro or hydroxy-Pro; Xaa at residue 15may be Lys, N-methyl-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Ly <221>NAME/KEY: PEPTIDE <222> LOCATION: (1)..(32) <223> OTHER INFORMATION: Xaaat residue 14 may be Trp or bromo-Trp; Xaa at residue 32 may be Tyr,mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Ty<400> SEQUENCE: 13 Asp Cys Xaa Ala Asp Gly Ala Phe Cys Gly Ile Xaa IleVal Xaa Asn 1 5 10 15 Xaa Met Cys Cys Ser Asn Leu Cys Ile Phe Ala CysVal Xaa Xaa Xaa 20 25 30 <210> SEQ ID NO 14 <211> LENGTH: 32 <212> TYPE:PRT <213> ORGANISM: Conus caracteristicus <220> FEATURE: <221> NAME/KEY:PEPTIDE <222> LOCATION: (1)..(32) <223> OTHER INFORMATION: Xaa atresidues 3 and 31 may be Glu or gamma-carboxy-Glu; Xaa at residues 12and 30 may be Pro or hydroxy-Pro; Xaa at residue 15 may be Lys,N-methyl-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Ly <221> NAME/KEY:PEPTIDE <222> LOCATION: (1)..(32) <223> OTHER INFORMATION: Xaa atresidue 14 may be Trp or bromo-Trp; Xaa at residue 32 may be Tyr,mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Ty<400> SEQUENCE: 14 Asp Cys Xaa Ala Asp Gly Ala Phe Cys Gly Ile Xaa ThrVal Xaa Asn 1 5 10 15 Xaa Met Cys Cys Ser Asn Leu Cys Ile Phe Ala CysVal Xaa Xaa Xaa 20 25 30 <210> SEQ ID NO 15 <211> LENGTH: 31 <212> TYPE:PRT <213> ORGANISM: Conus episcopatus <220> FEATURE: <221> NAME/KEY:PEPTIDE <222> LOCATION: (1)..(31) <223> OTHER INFORMATION: Xaa atresidues 4, 5 and 7 may be Glu or gamma-carboxy-Glu; Xaa at residue 6may be Trp or bromo-Trp; Xaa at residues 12, 21 and 27 may be Pro orhydroxy-Pro; Xaa at residue 18 may be Tyr, mono-halo-Tyr, <221>NAME/KEY: PEPTIDE <222> LOCATION: (1)..(31) <223> OTHER INFORMATION:di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr <400> SEQUENCE: 15Asp Cys Gly Xaa Xaa Xaa Xaa Phe Cys Ile Val Xaa Ile Leu Gly Phe 1 5 1015 Val Xaa Cys Cys Xaa Gly Leu Ile Cys Gly Xaa Phe Val Cys Val 20 25 30<210> SEQ ID NO 16 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM:Conus nobilis <220> FEATURE: <221> NAME/KEY: PEPTIDE <222> LOCATION:(1)..(31) <223> OTHER INFORMATION: Xaa at residue 7 may be Glu orgamma-carboxy-Glu; Xaa at residue 5 may be Lys, N-methyl-Lys,N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa at residue 6, 16 and 18 maybe Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr o <221>NAME/KEY: PEPTIDE <222> LOCATION: (1)..(31) <223> OTHER INFORMATION:nitro-Tyr; Xaa at residues 12 and 27 may be Pro or hydroxy-Pro <400>SEQUENCE: 16 Ala Cys Arg Gln Xaa Xaa Xaa Phe Cys Leu Val Xaa Ile Ile GlyXaa 1 5 10 15 Ile Xaa Cys Cys Ala Gly Leu Ile Cys Gly Xaa Phe Val CysLeu 20 25 30 <210> SEQ ID NO 17 <211> LENGTH: 36 <212> TYPE: PRT <213>ORGANISM: Conus tessulatus <220> FEATURE: <221> NAME/KEY: PEPTIDE <222>LOCATION: (1)..(36) <223> OTHER INFORMATION: Xaa at residues 1, 13, 33and 35 may be Pro or hydroxy-Pro; Xaa at residue 5, 8 and 34 may be Lys,N-methyl-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa at residue 6and 19 may be Tyr, mono-halo-Tyr, di-halo-Tyr, <221> NAME/KEY: PEPTIDE<222> LOCATION: (1)..(36) <223> OTHER INFORMATION: O-sulpho-Tyr,O-phospho-Tyr or nitro-Tyr <400> SEQUENCE: 17 Xaa Thr Cys Leu Xaa GlnAsp Xaa Phe Cys Ile Ile Xaa Leu Ile Gly 1 5 10 15 Thr Leu Xaa Cys CysSer Gly Leu Ile Cys Gly Phe Phe Val Cys Val 20 25 30 Xaa Xaa Xaa Phe 35<210> SEQ ID NO 18 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM:Conus tessulatus <220> FEATURE: <221> NAME/KEY: PEPTIDE <222> LOCATION:(1)..(31) <223> OTHER INFORMATION: Xaa at residues 1 and 13 is Pro orhydroxy-Pro; Xaa at residues 6 and 18 is Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phosp ho-Tyr or nitro-Ty <400> SEQUENCE: 18Xaa Thr Cys Val Ser Xaa Asn Val Phe Cys Gly Val Xaa Leu Val Gly 1 5 1015 Thr Xaa Leu Cys Cys Ser Gly Leu Val Cys Leu Val Val Cys Ile 20 25 30<210> SEQ ID NO 19 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM:Conus textile <220> FEATURE: <221> NAME/KEY: PEPTIDE <222> LOCATION:(1)..(31) <223> OTHER INFORMATION: Xaa at residues 4 and 21 is Glu orgamma-carboxy-Glu; Xaa at residues 6 and 8 is Trp or halo-Trp; Xaa atresidue 10 is Pro or hydroxy-Pro; Xaa at residue 18 is Tyr,mono-halo-Tyr, di-halo-Tyr, <221> NAME/KEY: PEPTIDE <222> LOCATION:(1)..(31) <223> OTHER INFORMATION: O-sulpho-Tyr, O-phospho-Tyr ornitro-Tyr <400> SEQUENCE: 19 Asp Cys His Xaa Arg Xaa Asp Xaa Cys Xaa AlaSer Ile Leu Gly Val 1 5 10 15 Ile Xaa Cys Cys Xaa Gly Leu Ile Cys PheIle Ala Phe Cys Ile 20 25 30 <210> SEQ ID NO 20 <211> LENGTH: 33 <212>TYPE: PRT <213> ORGANISM: Conus textile <220> FEATURE: <221> NAME/KEY:PEPTIDE <222> LOCATION: (1)..(33) <223> OTHER INFORMATION: Xaa atresidues 4 and 7 is Glu or gamma-carboxy-Glu; Xaa at residue 5 isLys,N-methy-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa at residue 6is Trp or halo-Trp; Xaa at residues 12, 21 and 2 <221> NAME/KEY: PEPTIDE<222> LOCATION: (1)..(33) <223> OTHER INFORMATION: is Pro orhydroxy-Pro; Xaa at residue 18 is Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr or nitro-Ty <400> SEQUENCE: 20 Asp Cys GlnXaa Xaa Xaa Xaa Phe Cys Ile Val Xaa Ile Leu Gly Phe 1 5 10 15 Val XaaCys Cys Xaa Gly Leu Ile Cys Gly Xaa Phe Val Cys Val Asp 20 25 30 Ile<210> SEQ ID NO 21 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:amplification primer <400> SEQUENCE: 21 caggatccat gaaactgacg tgyrtggtg29 <210> SEQ ID NO 22 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:amplification primer <400> SEQUENCE: 22 atctcgagca caggtatgga tgactcagg29 <210> SEQ ID NO 23 <211> LENGTH: 424 <212> TYPE: DNA <213> ORGANISM:Conus skinneri <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION:(1)..(264) <400> SEQUENCE: 23 atg aaa ctg acg tgt gtg gtg atc gtt gctgtg ctg ttc ttg acc gcc 48 Met Lys Leu Thr Cys Val Val Ile Val Ala ValLeu Phe Leu Thr Ala 1 5 10 15 tgg aca ttc gtc atg gct gat gac ccc agagat gga gcg gag att aga 96 Trp Thr Phe Val Met Ala Asp Asp Pro Arg AspGly Ala Glu Ile Arg 20 25 30 agc atg gta agg ggg gaa cct ctg tcg aag gcacgt gac gaa atg aac 144 Ser Met Val Arg Gly Glu Pro Leu Ser Lys Ala ArgAsp Glu Met Asn 35 40 45 ccc gaa gcc tct aaa ttg gag aaa agg gcg tgc cgccaa aaa tac gaa 192 Pro Glu Ala Ser Lys Leu Glu Lys Arg Ala Cys Arg GlnLys Tyr Glu 50 55 60 ttt tgt cta gta ccg atc att gga tac ata tat tgc tgcgct ggc tta 240 Phe Cys Leu Val Pro Ile Ile Gly Tyr Ile Tyr Cys Cys AlaGly Leu 65 70 75 80 atc tgt ggt cct ttc gtc tgc ctt tgatagtgatgtcttctact gccatctgtg 294 Ile Cys Gly Pro Phe Val Cys Leu 85 ctacccctggcttgatcttt gataggcgtt gttgcccttc actggtttat gaaccctctg 354 atcatactctctggaccctt gggggtccaa catccaaata aagcgacatc ccaaaaaaaa 414 aaaaaaaaaa424 <210> SEQ ID NO 24 <211> LENGTH: 88 <212> TYPE: PRT <213> ORGANISM:Conus skinneri <400> SEQUENCE: 24 Met Lys Leu Thr Cys Val Val Ile ValAla Val Leu Phe Leu Thr Ala 1 5 10 15 Trp Thr Phe Val Met Ala Asp AspPro Arg Asp Gly Ala Glu Ile Arg 20 25 30 Ser Met Val Arg Gly Glu Pro LeuSer Lys Ala Arg Asp Glu Met Asn 35 40 45 Pro Glu Ala Ser Lys Leu Glu LysArg Ala Cys Arg Gln Lys Tyr Glu 50 55 60 Phe Cys Leu Val Pro Ile Ile GlyTyr Ile Tyr Cys Cys Ala Gly Leu 65 70 75 80 Ile Cys Gly Pro Phe Val CysLeu 85 <210> SEQ ID NO 25 <211> LENGTH: 418 <212> TYPE: DNA <213>ORGANISM: Conus tessulatus <220> FEATURE: <221> NAME/KEY: CDS <222>LOCATION: (1)..(261) <400> SEQUENCE: 25 gga tcc atg aaa ctg acg tgc atggtg atc gtt gtt gtg ctg ttg ttg 48 Gly Ser Met Lys Leu Thr Cys Met ValIle Val Val Val Leu Leu Leu 1 5 10 15 aac gcc tgg aca ttc gtc tcc ataaat gga aag gcg aat cgt ttt tgg 96 Asn Ala Trp Thr Phe Val Ser Ile AsnGly Lys Ala Asn Arg Phe Trp 20 25 30 aag gca cgt gac gaa atg aag gac tccgaa gtt tct gaa ttg gag aaa 144 Lys Ala Arg Asp Glu Met Lys Asp Ser GluVal Ser Glu Leu Glu Lys 35 40 45 agg agg aaa ccg acc tgc ctg aag cag gacaag ttt tgc ata ata ccg 192 Arg Arg Lys Pro Thr Cys Leu Lys Gln Asp LysPhe Cys Ile Ile Pro 50 55 60 ctc att gga acc ctt tat tgc tgc agt ggg ttaatc tgt ggg ttt ttt 240 Leu Ile Gly Thr Leu Tyr Cys Cys Ser Gly Leu IleCys Gly Phe Phe 65 70 75 80 gtc tgc gtc cca aag ccg ttc tgatgtcttctactgccatc tgtgctaccc 291 Val Cys Val Pro Lys Pro Phe 85 ctggcttgatctttgattgg cgtgtgccct tcactggtta tgaacccctc tgatcctact 351 gtctggacgcctcgggcgtc caacgtccaa ataaagcgac atcccaataa aaaaaaaaaa 411 aaaaaaa 418<210> SEQ ID NO 26 <211> LENGTH: 87 <212> TYPE: PRT <213> ORGANISM:Conus tessulatus <400> SEQUENCE: 26 Gly Ser Met Lys Leu Thr Cys Met ValIle Val Val Val Leu Leu Leu 1 5 10 15 Asn Ala Trp Thr Phe Val Ser IleAsn Gly Lys Ala Asn Arg Phe Trp 20 25 30 Lys Ala Arg Asp Glu Met Lys AspSer Glu Val Ser Glu Leu Glu Lys 35 40 45 Arg Arg Lys Pro Thr Cys Leu LysGln Asp Lys Phe Cys Ile Ile Pro 50 55 60 Leu Ile Gly Thr Leu Tyr Cys CysSer Gly Leu Ile Cys Gly Phe Phe 65 70 75 80 Val Cys Val Pro Lys Pro Phe85 <210> SEQ ID NO 27 <211> LENGTH: 280 <212> TYPE: DNA <213> ORGANISM:Conus caracteristicus <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION:(1)..(249) <400> SEQUENCE: 27 atg aaa ctg acg tgc gtg atg atc gtt gctgtg ctg ttc ttg acc gcc 48 Met Lys Leu Thr Cys Val Met Ile Val Ala ValLeu Phe Leu Thr Ala 1 5 10 15 tgg aca ttc gtc acg gct gat gac tcc attaat gca ctg gag gat ctt 96 Trp Thr Phe Val Thr Ala Asp Asp Ser Ile AsnAla Leu Glu Asp Leu 20 25 30 ttt tcg aag gca cgt gac gaa atg gaa aac ggcgaa gct tct aca ttg 144 Phe Ser Lys Ala Arg Asp Glu Met Glu Asn Gly GluAla Ser Thr Leu 35 40 45 aac gag aga gac tgc gaa gca gat ggt gca ttt tgtggt atc cca att 192 Asn Glu Arg Asp Cys Glu Ala Asp Gly Ala Phe Cys GlyIle Pro Ile 50 55 60 gtg aag aac tgg atg tgc tgc agt aac ttg tgt att tttgcc tgc gta 240 Val Lys Asn Trp Met Cys Cys Ser Asn Leu Cys Ile Phe AlaCys Val 65 70 75 80 ccc gag tat taagactgcc gtgatgtctt ctcctcccct c 280Pro Glu Tyr <210> SEQ ID NO 28 <211> LENGTH: 83 <212> TYPE: PRT <213>ORGANISM: Conus caracteristicus <400> SEQUENCE: 28 Met Lys Leu Thr CysVal Met Ile Val Ala Val Leu Phe Leu Thr Ala 1 5 10 15 Trp Thr Phe ValThr Ala Asp Asp Ser Ile Asn Ala Leu Glu Asp Leu 20 25 30 Phe Ser Lys AlaArg Asp Glu Met Glu Asn Gly Glu Ala Ser Thr Leu 35 40 45 Asn Glu Arg AspCys Glu Ala Asp Gly Ala Phe Cys Gly Ile Pro Ile 50 55 60 Val Lys Asn TrpMet Cys Cys Ser Asn Leu Cys Ile Phe Ala Cys Val 65 70 75 80 Pro Glu Tyr<210> SEQ ID NO 29 <211> LENGTH: 132 <212> TYPE: DNA <213> ORGANISM:Conus textile <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION:(2)..(106) <400> SEQUENCE: 29 a ttg gag aaa agg gat tgc cac gaa agg tgggat tgg tgt cca gca tca 49 Leu Glu Lys Arg Asp Cys His Glu Arg Trp AspTrp Cys Pro Ala Ser 1 5 10 15 atc ctt gga gtg ata tat tgc tgc gag ggatta att tgt ttt att gcc 97 Ile Leu Gly Val Ile Tyr Cys Cys Glu Gly LeuIle Cys Phe Ile Ala 20 25 30 ttc tgc att tgatagtgat gtcttctcct cccctc132 Phe Cys Ile 35 <210> SEQ ID NO 30 <211> LENGTH: 35 <212> TYPE: PRT<213> ORGANISM: Conus textile <400> SEQUENCE: 30 Leu Glu Lys Arg Asp CysHis Glu Arg Trp Asp Trp Cys Pro Ala Ser 1 5 10 15 Ile Leu Gly Val IleTyr Cys Cys Glu Gly Leu Ile Cys Phe Ile Ala 20 25 30 Phe Cys Ile 35<210> SEQ ID NO 31 <211> LENGTH: 132 <212> TYPE: DNA <213> ORGANISM:Conus textile <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION:(2)..(112) <400> SEQUENCE: 31 a ttg gag aaa agg gat tgc caa gag aaa tgggag ttt tgt ata gta ccg 49 Leu Glu Lys Arg Asp Cys Gln Glu Lys Trp GluPhe Cys Ile Val Pro 1 5 10 15 atc ctt gga ttt gta tat tgc tgc cct ggctta atc tgt ggc cct ttt 97 Ile Leu Gly Phe Val Tyr Cys Cys Pro Gly LeuIle Cys Gly Pro Phe 20 25 30 gtc tgc gtt gat atc tgatgtcttc tcctcccatc132 Val Cys Val Asp Ile 35 <210> SEQ ID NO 32 <211> LENGTH: 37 <212>TYPE: PRT <213> ORGANISM: Conus textile <400> SEQUENCE: 32 Leu Glu LysArg Asp Cys Gln Glu Lys Trp Glu Phe Cys Ile Val Pro 1 5 10 15 Ile LeuGly Phe Val Tyr Cys Cys Pro Gly Leu Ile Cys Gly Pro Phe 20 25 30 Val CysVal Asp Ile 35 <210> SEQ ID NO 33 <211> LENGTH: 288 <212> TYPE: DNA<213> ORGANISM: Conus tessulatus <220> FEATURE: <221> NAME/KEY: CDS<222> LOCATION: (7)..(246) <400> SEQUENCE: 33 ggatcc atg aaa ctg acg tgtgtg gtg atc gtt gtt gtg ctg ttg ttg 48 Met Lys Leu Thr Cys Val Val IleVal Val Val Leu Leu Leu 1 5 10 aac gcc tgg aca ttc gtc tcc ata aat ggaaag gcg aat cct ttt tgg 96 Asn Ala Trp Thr Phe Val Ser Ile Asn Gly LysAla Asn Pro Phe Trp 15 20 25 30 aag gca cgt gac gaa atg aag gac tcc gaagtt tct gag ttg gag aaa 144 Lys Ala Arg Asp Glu Met Lys Asp Ser Glu ValSer Glu Leu Glu Lys 35 40 45 agg agg aaa ccg acc tgc gtg tcg tat aac gtgttt tgc gga gta ccg 192 Arg Arg Lys Pro Thr Cys Val Ser Tyr Asn Val PheCys Gly Val Pro 50 55 60 ctc gtt gga acc tac ctt tgc tgc agt ggc tta gtctgt ctc gta gtc 240 Leu Val Gly Thr Tyr Leu Cys Cys Ser Gly Leu Val CysLeu Val Val 65 70 75 tgc atc tagtactgat gtcttctact cccatctgtg ctacccctcgag 288 Cys Ile 80 <210> SEQ ID NO 34 <211> LENGTH: 80 <212> TYPE: PRT<213> ORGANISM: Conus tessulatus <400> SEQUENCE: 34 Met Lys Leu Thr CysVal Val Ile Val Val Val Leu Leu Leu Asn Ala 1 5 10 15 Trp Thr Phe ValSer Ile Asn Gly Lys Ala Asn Pro Phe Trp Lys Ala 20 25 30 Arg Asp Glu MetLys Asp Ser Glu Val Ser Glu Leu Glu Lys Arg Arg 35 40 45 Lys Pro Thr CysVal Ser Tyr Asn Val Phe Cys Gly Val Pro Leu Val 50 55 60 Gly Thr Tyr LeuCys Cys Ser Gly Leu Val Cys Leu Val Val Cys Ile 65 70 75 80 <210> SEQ IDNO 35 <211> LENGTH: 287 <212> TYPE: DNA <213> ORGANISM: Conus atlanticus<220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (7)..(240) <400>SEQUENCE: 35 ggatcc atg aaa ctg acg tgc gtg gtg atc gtt gct gtg ctg ttcttg 48 Met Lys Leu Thr Cys Val Val Ile Val Ala Val Leu Phe Leu 1 5 10acc gcc tgg aca ttc gtc acg gct gat gac tcc ata aat ggg ttg gag 96 ThrAla Trp Thr Phe Val Thr Ala Asp Asp Ser Ile Asn Gly Leu Glu 15 20 25 30aat ctt ttt ccg aag gca cgt cac gaa atg agg aaa ccc gaa gcc tct 144 AsnLeu Phe Pro Lys Ala Arg His Glu Met Arg Lys Pro Glu Ala Ser 35 40 45 agatcg aga ggg agg tgc cgt cct cgt ggt atg ttc tgt ggc ttt ccg 192 Arg SerArg Gly Arg Cys Arg Pro Arg Gly Met Phe Cys Gly Phe Pro 50 55 60 aaa cctgga cca tac tgc tgc aat ggc tgg tgc ttt ttc gtc tgc atc 240 Lys Pro GlyPro Tyr Cys Cys Asn Gly Trp Cys Phe Phe Val Cys Ile 65 70 75 taaaactgccgtgatgtgtt ctactcccat ctgtgctacc cctcgag 287 <210> SEQ ID NO 36 <211>LENGTH: 78 <212> TYPE: PRT <213> ORGANISM: Conus atlanticus <400>SEQUENCE: 36 Met Lys Leu Thr Cys Val Val Ile Val Ala Val Leu Phe Leu ThrAla 1 5 10 15 Trp Thr Phe Val Thr Ala Asp Asp Ser Ile Asn Gly Leu GluAsn Leu 20 25 30 Phe Pro Lys Ala Arg His Glu Met Arg Lys Pro Glu Ala SerArg Ser 35 40 45 Arg Gly Arg Cys Arg Pro Arg Gly Met Phe Cys Gly Phe ProLys Pro 50 55 60 Gly Pro Tyr Cys Cys Asn Gly Trp Cys Phe Phe Val Cys Ile65 70 75 <210> SEQ ID NO 37 <211> LENGTH: 289 <212> TYPE: DNA <213>ORGANISM: Conus tessulatus <220> FEATURE: <221> NAME/KEY: CDS <222>LOCATION: (7)..(249) <400> SEQUENCE: 37 ggatcc atg aaa ctg acg tgc gtggtg gtc gtt gct gtg ctg ttc ttg 48 Met Lys Leu Thr Cys Val Val Val ValAla Val Leu Phe Leu 1 5 10 aac gcc tgg aca ttc gcc acg gct gtt gac tccaaa cat gca ctg gcg 96 Asn Ala Trp Thr Phe Ala Thr Ala Val Asp Ser LysHis Ala Leu Ala 15 20 25 30 aaa ctt ttt atg aag gca cgt gac gaa atg tataac ccc gat gcc act 144 Lys Leu Phe Met Lys Ala Arg Asp Glu Met Tyr AsnPro Asp Ala Thr 35 40 45 aaa ttg gac gat aag aga tgg tgc gct tta gat ggtgaa ctt tgt atc 192 Lys Leu Asp Asp Lys Arg Trp Cys Ala Leu Asp Gly GluLeu Cys Ile 50 55 60 ata ccg gtc att ggg tcc ata ttt tgc tgc cat ggc atatgt atg atc 240 Ile Pro Val Ile Gly Ser Ile Phe Cys Cys His Gly Ile CysMet Ile 65 70 75 tac tgc gtc tagttgaact gccgtgatgt cttctactcc cctctgtgct289 Tyr Cys Val 80 <210> SEQ ID NO 38 <211> LENGTH: 81 <212> TYPE: PRT<213> ORGANISM: Conus tessulatus <400> SEQUENCE: 38 Met Lys Leu Thr CysVal Val Val Val Ala Val Leu Phe Leu Asn Ala 1 5 10 15 Trp Thr Phe AlaThr Ala Val Asp Ser Lys His Ala Leu Ala Lys Leu 20 25 30 Phe Met Lys AlaArg Asp Glu Met Tyr Asn Pro Asp Ala Thr Lys Leu 35 40 45 Asp Asp Lys ArgTrp Cys Ala Leu Asp Gly Glu Leu Cys Ile Ile Pro 50 55 60 Val Ile Gly SerIle Phe Cys Cys His Gly Ile Cys Met Ile Tyr Cys 65 70 75 80 Val <210>SEQ ID NO 39 <211> LENGTH: 340 <212> TYPE: DNA <213> ORGANISM: Conusarenatus <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (7)..(246)<221> NAME/KEY: misc_feature <222> LOCATION: (1)..(340) <223> OTHERINFORMATION: n may be any nucleotide <400> SEQUENCE: 39 ggatcc atg aaactg acg tgt gtg gtg atc gtt gct gtg ctg ttc ttg 48 Met Lys Leu Thr CysVal Val Ile Val Ala Val Leu Phe Leu 1 5 10 acc gcc tgg aca ttc gtc acggct gac tcc ata cgt gca ctg gag gat 96 Thr Ala Trp Thr Phe Val Thr AlaAsp Ser Ile Arg Ala Leu Glu Asp 15 20 25 30 ttt ttt gcg aag gca cgt gacgaa atg gaa aac agc gga gct tct cca 144 Phe Phe Ala Lys Ala Arg Asp GluMet Glu Asn Ser Gly Ala Ser Pro 35 40 45 ttg aac gag aga gac tgc cga cctgta ggt caa tat tgt ggc ata ccg 192 Leu Asn Glu Arg Asp Cys Arg Pro ValGly Gln Tyr Cys Gly Ile Pro 50 55 60 tat aag cac aac tgg cga tgc tgc agtcag ctt tgt gca att atc tgt 240 Tyr Lys His Asn Trp Arg Cys Cys Ser GlnLeu Cys Ala Ile Ile Cys 65 70 75 gtt tcc taacccctct gatcctactctctgaagacc tccgggattc aacatccaaa 296 Val Ser 80 taaagcgaca tcccgatnaaaaaaaangaa aaaaaaaaaa aaaa 340 <210> SEQ ID NO 40 <211> LENGTH: 80 <212>TYPE: PRT <213> ORGANISM: Conus arenatus <220> FEATURE: <221> NAME/KEY:misc_feature <222> LOCATION: (1)..(340) <223> OTHER INFORMATION: n maybe any nucleotide <400> SEQUENCE: 40 Met Lys Leu Thr Cys Val Val Ile ValAla Val Leu Phe Leu Thr Ala 1 5 10 15 Trp Thr Phe Val Thr Ala Asp SerIle Arg Ala Leu Glu Asp Phe Phe 20 25 30 Ala Lys Ala Arg Asp Glu Met GluAsn Ser Gly Ala Ser Pro Leu Asn 35 40 45 Glu Arg Asp Cys Arg Pro Val GlyGln Tyr Cys Gly Ile Pro Tyr Lys 50 55 60 His Asn Trp Arg Cys Cys Ser GlnLeu Cys Ala Ile Ile Cys Val Ser 65 70 75 80 <210> SEQ ID NO 41 <211>LENGTH: 293 <212> TYPE: DNA <213> ORGANISM: Conus generalis <220>FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (7)..(249) <400> SEQUENCE:41 ggatcc atg aaa ctg acg tgt gtg gtg atc gtt gct gtg cta ttc ttg 48 MetLys Leu Thr Cys Val Val Ile Val Ala Val Leu Phe Leu 1 5 10 acc gcc tggaca ttc gtc acg gct gat gac acc aga tat aaa ctg gag 96 Thr Ala Trp ThrPhe Val Thr Ala Asp Asp Thr Arg Tyr Lys Leu Glu 15 20 25 30 aat cct tttctg aag gca cgc aac gaa ctg cag aaa cac gaa gcc tct 144 Asn Pro Phe LeuLys Ala Arg Asn Glu Leu Gln Lys His Glu Ala Ser 35 40 45 caa ctg aac gagaga ggc tgc ctt gac cca ggt tac ttc tgt ggg acg 192 Gln Leu Asn Glu ArgGly Cys Leu Asp Pro Gly Tyr Phe Cys Gly Thr 50 55 60 ccg ttt ctt gga gcatac tgc tgc ggt ggc att tgc ctt att gtc tgc 240 Pro Phe Leu Gly Ala TyrCys Cys Gly Gly Ile Cys Leu Ile Val Cys 65 70 75 ata gaa acg taaaggcttgatgtcttcta ctcccatctg tgctacccct cgag 293 Ile Glu Thr 80 <210> SEQ ID NO42 <211> LENGTH: 81 <212> TYPE: PRT <213> ORGANISM: Conus generalis<400> SEQUENCE: 42 Met Lys Leu Thr Cys Val Val Ile Val Ala Val Leu PheLeu Thr Ala 1 5 10 15 Trp Thr Phe Val Thr Ala Asp Asp Thr Arg Tyr LysLeu Glu Asn Pro 20 25 30 Phe Leu Lys Ala Arg Asn Glu Leu Gln Lys His GluAla Ser Gln Leu 35 40 45 Asn Glu Arg Gly Cys Leu Asp Pro Gly Tyr Phe CysGly Thr Pro Phe 50 55 60 Leu Gly Ala Tyr Cys Cys Gly Gly Ile Cys Leu IleVal Cys Ile Glu 65 70 75 80 Thr <210> SEQ ID NO 43 <211> LENGTH: 280<212> TYPE: DNA <213> ORGANISM: Conus caracteristicus <400> SEQUENCE: 43atgaaactga cgtgcgtgat gatcgttgct gtgctgttct tgaccgcctg gacattcgtc 60acggctgatg actccattaa tgcactggag gatctttttt cgaaggcacg tgacgaaatg 120gaaaacggcg aagcttctac attgaacgag agagactgcg aagcagatgg tgcattttgt 180ggtatcccaa ttgtgaagaa ctggatgtgc tgcagtaact tgtgtatttt tgcctgcgta 240cccgagtatt aagactgccg tgatgtcttc tcctcccctc 280 <210> SEQ ID NO 44 <211>LENGTH: 83 <212> TYPE: PRT <213> ORGANISM: Conus caracteristicus <400>SEQUENCE: 44 Met Lys Leu Thr Cys Val Met Ile Val Ala Val Leu Phe Leu ThrAla 1 5 10 15 Trp Thr Phe Val Thr Ala Asp Asp Ser Ile Asn Ala Leu GluAsp Leu 20 25 30 Phe Ser Lys Ala Arg Asp Glu Met Glu Asn Gly Glu Ala SerThr Leu 35 40 45 Asn Glu Arg Asp Cys Glu Ala Asp Gly Ala Phe Cys Gly IlePro Ile 50 55 60 Val Lys Asn Trp Met Cys Cys Ser Asn Leu Cys Ile Phe AlaCys Val 65 70 75 80 Pro Glu Tyr <210> SEQ ID NO 45 <211> LENGTH: 32<212> TYPE: PRT <213> ORGANISM: Conus caracteristicus <220> FEATURE:<221> NAME/KEY: PEPTIDE <222> LOCATION: (1)..(32) <223> OTHERINFORMATION: Xaa at residue 3 and 31is Glu or gamma-carboxy Glu; Xaa atresidue 12 and 30 is Pro or Hydroxy Pro; Xaa at residue 17 is Trp orBromo Trp; Xaa at residue 32 is Tyr, 125I-Tyr, Mono-Iodo Tyr, Di-IodoTyr, O-sulpho-Tyr or O-Phospho-Ty <400> SEQUENCE: 45 Asp Cys Xaa Ala AspGly Ala Phe Cys Gly Ile Xaa Ile Val Lys Asn 1 5 10 15 Xaa Met Cys CysSer Asn Leu Cys Ile Phe Ala Cys Val Xaa Xaa Xaa 20 25 30 <210> SEQ ID NO46 <211> LENGTH: 424 <212> TYPE: DNA <213> ORGANISM: Conus nobilis <400>SEQUENCE: 46 atgaaactga cgtgtgtggt gatcgttgct gtgctgttct tgaccgcctggacattcgtc 60 atggctgatg accccagaga tggagcggag attagaagca tggtaaggggggaacctctg 120 tcgaaggcac gtgacgaaat gaaccccgaa gcctctaaat tggagaaaagggcgtgccgc 180 caaaaatacg aattttgtct agtaccgatc attggataca tatattgctgcgctggctta 240 atctgtggtc ctttcgtctg cctttgatag tgatgtcttc tactgccatctgtgctaccc 300 ctggcttgat ctttgatagg cgttgttgcc cttcactggt ttatgaaccctctgatcata 360 ctctctggac ccttgggggt ccaacatcca aataaagcga catcccaaaaaaaaaaaaaa 420 aaaa 424 <210> SEQ ID NO 47 <211> LENGTH: 88 <212> TYPE:PRT <213> ORGANISM: Conus nobilis <400> SEQUENCE: 47 Met Lys Leu Thr CysVal Val Ile Val Ala Val Leu Phe Leu Thr Ala 1 5 10 15 Trp Thr Phe ValMet Ala Asp Asp Pro Arg Asp Gly Ala Glu Ile Arg 20 25 30 Ser Met Val ArgGly Glu Pro Leu Ser Lys Ala Arg Asp Glu Met Asn 35 40 45 Pro Glu Ala SerLys Leu Glu Lys Arg Ala Cys Arg Gln Lys Tyr Glu 50 55 60 Phe Cys Leu ValPro Ile Ile Gly Tyr Ile Tyr Cys Cys Ala Gly Leu 65 70 75 80 Ile Cys GlyPro Phe Val Cys Leu 85 <210> SEQ ID NO 48 <211> LENGTH: 31 <212> TYPE:PRT <213> ORGANISM: Conus nobilis <220> FEATURE: <221> NAME/KEY: PEPTIDE<222> LOCATION: (1)..(31) <223> OTHER INFORMATION: Xaa at residue 7 31isGlu or gamma-carboxy Glu; Xaa at residue 12 and 27 is Pro or HydroxyPro; Xaa at residue 6, 16 and 18 is Tyr, 125I-Tyr, Mono-Iodo Tyr,Di-Iodo Tyr, O-sulpho-Tyr or O-Phospho-Ty <400> SEQUENCE: 48 Ala Cys ArgGln Lys Xaa Xaa Phe Cys Leu Val Xaa Ile Ile Gly Xaa 1 5 10 15 Ile XaaCys Cys Ala Gly Leu Ile Cys Gly Xaa Phe Val Cys Leu 20 25 30 <210> SEQID NO 49 <211> LENGTH: 132 <212> TYPE: DNA <213> ORGANISM: Conus textile<400> SEQUENCE: 49 attggagaaa agggattgcc acgaaaggtg ggattggtgtccagcatcaa tccttggagt 60 gatatattgc tgcgagggat taatttgttt tattgccttctgcatttgat agtgatgtct 120 tctcctcccc tc 132 <210> SEQ ID NO 50 <211>LENGTH: 35 <212> TYPE: PRT <213> ORGANISM: Conus textile <400> SEQUENCE:50 Leu Glu Lys Arg Asp Cys His Glu Arg Trp Asp Trp Cys Pro Ala Ser 1 510 15 Ile Leu Gly Val Ile Tyr Cys Cys Glu Gly Leu Ile Cys Phe Ile Ala 2025 30 Phe Cys Ile 35 <210> SEQ ID NO 51 <211> LENGTH: 31 <212> TYPE: PRT<213> ORGANISM: Conus textile <220> FEATURE: <221> NAME/KEY: PEPTIDE<222> LOCATION: (1)..(31) <223> OTHER INFORMATION: Xaa at residue 4 and21 is Glu or gamma-carboxy Glu; Xaa at residue 10 is Pro or Hydroxy Pro;Xaa at residue 6 and 8 is Trp or Bromo Trp; Xaa at residue 18 is Tyr,125I-Tyr, Mono-Iodo Tyr, Di-Iodo Tyr, O-sulpho-Tyr or O-Phospho-Ty <400>SEQUENCE: 51 Asp Cys His Xaa Arg Xaa Asp Xaa Cys Xaa Ala Ser Ile Leu GlyVal 1 5 10 15 Ile Xaa Cys Cys Xaa Gly Leu Ile Cys Phe Ile Ala Phe CysIle 20 25 30 <210> SEQ ID NO 52 <211> LENGTH: 132 <212> TYPE: DNA <213>ORGANISM: Conus textile <400> SEQUENCE: 52 attggagaaa agggattgccaagagaaatg ggagttttgt atagtaccga tccttggatt 60 tgtatattgc tgccctggcttaatctgtgg cccttttgtc tgcgttgata tctgatgtct 120 tctcctccca tc 132 <210>SEQ ID NO 53 <211> LENGTH: 37 <212> TYPE: PRT <213> ORGANISM: Conustextile <400> SEQUENCE: 53 Leu Glu Lys Arg Asp Cys Gln Glu Lys Trp GluPhe Cys Ile Val Pro 1 5 10 15 Ile Leu Gly Phe Val Tyr Cys Cys Pro GlyLeu Ile Cys Gly Pro Phe 20 25 30 Val Cys Val Asp Ile 35 <210> SEQ ID NO54 <211> LENGTH: 33 <212> TYPE: PRT <213> ORGANISM: Conus textile <220>FEATURE: <221> NAME/KEY: PEPTIDE <222> LOCATION: (1)..(33) <223> OTHERINFORMATION: Xaa at residue 4 and 7 is Glu or gamma-carboxy Glu; Xaa atresidue 12, 21 and 27 is Pro or Hydroxy Pro; Xaa at residue 6 is Trp orBromo Trp; Xaa at residue 18 is Tyr, 125I-Tyr, Mono-Iodo Tyr, Di-IodoTyr, O-sulpho-Tyr or O-Phospho-Ty <400> SEQUENCE: 54 Asp Cys Gln Xaa LysXaa Xaa Phe Cys Ile Val Xaa Ile Leu Gly Phe 1 5 10 15 Val Xaa Cys CysXaa Gly Leu Ile Cys Gly Xaa Phe Val Cys Val Asp 20 25 30 Ile <210> SEQID NO 55 <211> LENGTH: 418 <212> TYPE: DNA <213> ORGANISM: Conustessulatus <400> SEQUENCE: 55 ggatccatga aactgacgtg catggtgatcgttgttgtgc tgttgttgaa cgcctggaca 60 ttcgtctcca taaatggaaa ggcgaatcgtttttggaagg cacgtgacga aatgaaggac 120 tccgaagttt ctgaattgga gaaaaggaggaaaccgacct gcctgaagca ggacaagttt 180 tgcataatac cgctcattgg aaccctttattgctgcagtg ggttaatctg tgggtttttt 240 gtctgcgtcc caaagccgtt ctgatgtcttctactgccat ctgtgctacc cctggcttga 300 tctttgattg gcgtgtgccc ttcactggttatgaacccct ctgatcctac tgtctggacg 360 cctcgggcgt ccaacgtcca aataaagcgacatcccaata aaaaaaaaaa aaaaaaaa 418 <210> SEQ ID NO 56 <211> LENGTH: 85<212> TYPE: PRT <213> ORGANISM: Conus tessulatus <400> SEQUENCE: 56 MetLys Leu Thr Cys Met Val Ile Val Val Val Leu Leu Leu Asn Ala 1 5 10 15Trp Thr Phe Val Ser Ile Asn Gly Lys Ala Asn Arg Phe Trp Lys Ala 20 25 30Arg Asp Glu Met Lys Asp Ser Glu Val Ser Glu Leu Glu Lys Arg Arg 35 40 45Lys Pro Thr Cys Leu Lys Gln Asp Lys Phe Cys Ile Ile Pro Leu Ile 50 55 60Gly Thr Leu Tyr Cys Cys Ser Gly Leu Ile Cys Gly Phe Phe Val Cys 65 70 7580 Val Pro Lys Pro Phe 85 <210> SEQ ID NO 57 <211> LENGTH: 36 <212>TYPE: PRT <213> ORGANISM: Conus tessulatus <220> FEATURE: <221>NAME/KEY: PEPTIDE <222> LOCATION: (1)..(36) <223> OTHER INFORMATION: Xaaat residue 1, 13, 33 and 35 is Pro or Hydroxy Pro; Xaa at residue 19 isTyr, 125I-Tyr, Mono-Iodo Tyr, Di-Iodo Tyr, O-sulpho-Tyr or O-Phospho-Ty<400> SEQUENCE: 57 Xaa Thr Cys Leu Lys Gln Asp Lys Phe Cys Ile Ile XaaLeu Ile Gly 1 5 10 15 Thr Leu Xaa Cys Cys Ser Gly Leu Ile Cys Gly PhePhe Val Cys Val 20 25 30 Xaa Lys Xaa Phe 35 <210> SEQ ID NO 58 <211>LENGTH: 288 <212> TYPE: DNA <213> ORGANISM: Conus tessulatus <400>SEQUENCE: 58 ggatccatga aactgacgtg tgtggtgatc gttgttgtgc tgttgttgaacgcctggaca 60 ttcgtctcca taaatggaaa ggcgaatcct ttttggaagg cacgtgacgaaatgaaggac 120 tccgaagttt ctgagttgga gaaaaggagg aaaccgacct gcgtgtcgtataacgtgttt 180 tgcggagtac cgctcgttgg aacctacctt tgctgcagtg gcttagtctgtctcgtagtc 240 tgcatctagt actgatgtct tctactccca tctgtgctac ccctcgag 288<210> SEQ ID NO 59 <211> LENGTH: 80 <212> TYPE: PRT <213> ORGANISM:Conus tessulatus <400> SEQUENCE: 59 Met Lys Leu Thr Cys Val Val Ile ValVal Val Leu Leu Leu Asn Ala 1 5 10 15 Trp Thr Phe Val Ser Ile Asn GlyLys Ala Asn Pro Phe Trp Lys Ala 20 25 30 Arg Asp Glu Met Lys Asp Ser GluVal Ser Glu Leu Glu Lys Arg Arg 35 40 45 Lys Pro Thr Cys Val Ser Tyr AsnVal Phe Cys Gly Val Pro Leu Val 50 55 60 Gly Thr Tyr Leu Cys Cys Ser GlyLeu Val Cys Leu Val Val Cys Ile 65 70 75 80 <210> SEQ ID NO 60 <211>LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Conus tessulatus <220>FEATURE: <221> NAME/KEY: PEPTIDE <222> LOCATION: (1)..(31) <223> OTHERINFORMATION: Xaa at residue 1 and 13 is Pro or Hydroxy Pro; Xaa atresidue 6 and 18 is Tyr, 125I-Tyr, Mono-Iodo Tyr, Di-Iodo Tyr,O-sulpho-Tyr or O-Phospho-Ty <400> SEQUENCE: 60 Xaa Thr Cys Val Ser XaaAsn Val Phe Cys Gly Val Xaa Leu Val Gly 1 5 10 15 Thr Xaa Leu Cys CysSer Gly Leu Val Cys Leu Val Val Cys Ile 20 25 30 <210> SEQ ID NO 61<211> LENGTH: 357 <212> TYPE: DNA <213> ORGANISM: Conus caracteristicus<400> SEQUENCE: 61 ggatccatga aactgacgtg catggtgatc gttgctgtgctgttcttgac cgcctggaca 60 ttcgtcacgg ctgatgactc cattaatgca ctggaggatcttttttcgaa ggcacgcgac 120 gaaatggaaa acggcgaagc ttctacattg aacgagagagactgcgaagc agatggtgca 180 ttttgtggta tcccaactgt gaagaactgg atgtgctgcagtaacttgtg tatttttgcc 240 tgcgtacccg agtattaaga ctgccgtgat gtcttctgctcccctctgtg ctacctggct 300 tgatctttga ttggcgcgtg cccttcactg gttatgaacccctctgatcc tactctc 357 <210> SEQ ID NO 62 <211> LENGTH: 83 <212> TYPE:PRT <213> ORGANISM: Conus caracteristicus <400> SEQUENCE: 62 Met Lys LeuThr Cys Met Val Ile Val Ala Val Leu Phe Leu Thr Ala 1 5 10 15 Trp ThrPhe Val Thr Ala Asp Asp Ser Ile Asn Ala Leu Glu Asp Leu 20 25 30 Phe SerLys Ala Arg Asp Glu Met Glu Asn Gly Glu Ala Ser Thr Leu 35 40 45 Asn GluArg Asp Cys Glu Ala Asp Gly Ala Phe Cys Gly Ile Pro Thr 50 55 60 Val LysAsn Trp Met Cys Cys Ser Asn Leu Cys Ile Phe Ala Cys Val 65 70 75 80 ProGlu Tyr <210> SEQ ID NO 63 <211> LENGTH: 32 <212> TYPE: PRT <213>ORGANISM: Conus caracteristicus <220> FEATURE: <221> NAME/KEY: PEPTIDE<222> LOCATION: (1)..(32) <223> OTHER INFORMATION: Xaa at residue 3 and31 is Glu or gamma-carboxy Glu; Xaa at residue 12 and 30 is Pro orHydroxy Pro; Xaa at residue 17 is Trp or Bromo Trp; Xaa at residue 32 isTyr, 125I-Tyr, Mono-Iodo Tyr, Di-Iodo Tyr, O-sulpho-Tyr or O-Phospho-Ty<400> SEQUENCE: 63 Asp Cys Xaa Ala Asp Gly Ala Phe Cys Gly Ile Xaa ThrVal Lys Asn 1 5 10 15 Xaa Met Cys Cys Ser Asn Leu Cys Ile Phe Ala CysVal Xaa Xaa Xaa 20 25 30 <210> SEQ ID NO 64 <211> LENGTH: 409 <212>TYPE: DNA <213> ORGANISM: Conus episcopatus <220> FEATURE: <221>NAME/KEY: misc_feature <222> LOCATION: (1)..(409) <223> OTHERINFORMATION: n may be any nucleotide <400> SEQUENCE: 64 ggatccatgaaactgacgtg tgtggtgatc attgctgtgc tgttcttgac cgcctggaca 60 ttcgtcatggctgatgactc caacaatgga ctggcgaatc atttttcgaa atcacgtgac 120 gaaatggaggaccccgaagc ttctaaattg gagaaaagaa gggattgcca agaagaatgg 180 gaattttgtatagtaccgat ccttggattc gtatattgct gccctggctt aatctgtggt 240 cctttcgtctgcgtttaata ctgatgtctt ctactcccat ctgtgctaca cctggcttga 300 tctttgataggcgtgtgccc ttcactggtt ataaacccct ctgatcctac tctctggacg 360 cctcgggggcccaacatcca aataaagcaa catcccaatg aanaaaaaa 409 <210> SEQ ID NO 65 <211>LENGTH: 83 <212> TYPE: PRT <213> ORGANISM: Conus episcopatus <400>SEQUENCE: 65 Met Lys Leu Thr Cys Val Val Ile Ile Ala Val Leu Phe Leu ThrAla 1 5 10 15 Trp Thr Phe Val Met Ala Asp Asp Ser Asn Asn Gly Leu AlaAsn His 20 25 30 Phe Ser Lys Ser Arg Asp Glu Met Glu Asp Pro Glu Ala SerLys Leu 35 40 45 Glu Lys Arg Arg Asp Cys Gln Glu Glu Trp Glu Phe Cys IleVal Pro 50 55 60 Ile Leu Gly Phe Val Tyr Cys Cys Pro Gly Leu Ile Cys GlyPro Phe 65 70 75 80 Val Cys Val <210> SEQ ID NO 66 <211> LENGTH: 31<212> TYPE: PRT <213> ORGANISM: Conus episcopatus <220> FEATURE: <221>NAME/KEY: PEPTIDE <222> LOCATION: (1)..(31) <223> OTHER INFORMATION: Xaaat residue 4, 5 and 7 is Glu or gamma-carboxy Glu; Xaa at residue 12, 21and 27 is Pro or Hydroxy Pro; Xaa at residue 6 is Trp or Bromo Trp; Xaaat residue 18 is Tyr, 125I-Tyr, Mono-Iodo Tyr, Di-Iodo Tyr, O-sulpho-Tyror O-Phospho-Ty <400> SEQUENCE: 66 Asp Cys Gln Xaa Xaa Xaa Xaa Phe CysIle Val Xaa Ile Leu Gly Phe 1 5 10 15 Val Xaa Cys Cys Xaa Gly Leu IleCys Gly Xaa Phe Val Cys Val 20 25 30

What is claimed is:
 1. A method of alleviating pain which comprisesadministering to a mammal that is either exhibiting pain or is about tobe subjected to a pain-causing event a pain-alleviating amount of anactive agent comprising a μO-conopeptide, derivative or pharmaceuticallyacceptable salt or solvate thereof.
 2. The method of claim 1, whereinsaid μO-conopeptide has the general formula I:Xaa₁-Xaa₂-Cys-Xaa₃-Xaa₄-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Cys-Xaa₉-Xaa₁₀-Xaa₁₁-Xaa₁₂-Xaa₁₃-Xaa₁₄-Xaa₁₅-Xaa₁₆-Xaa₁₇-Cys-Cys-Xaa₁₈-Xaa₁₉-Xaa₂₀-Xaa₂₁-(ys-Xaa₂₂-Xaa₂₃-Xaa₂₄-Xaa₂₅-Cys-Xaa₂₆-Xaa₂₇-Xaa₂₈-Xaa₂₉-Xaa₃₀(SEQ ID NO:1), wherein Xaa₁ is des-Xaa₁, Pro, hydroxy-Pro (Hyp), Arg,Lys, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any synthetic basic aminoacid; Xaa₂ is des-Xaa₂, Ala, Gly, Asp, Glu, γ-carboxy-glutamate (Gla),any synthetic acidic amino acid, Thr, Ser, g-Thr (where g isglycosylation), g-Ser, Trp (D or L), neo-Trp or halo-Trp (D or L) orXaa₂ may be pyroglutamate if Xaa₁ is des-Xaa₁; Xaa₃ is Arg, Lys,ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any synthetic basic aminoacid, Ser, Thr, g-Ser, g-Thr, Ala, an aliphatic amino acid bearinglinear or branched saturated hydrocarbon chains such as Leu (D or L),Ile and Val or non-natural derivatives of the aliphatic amino acid, His,Glu, Gln, Gla, Asp, Asn or any synthetic acidic amino acid; Xaa₄ is Glu,Gla, Gln, Asp, Asn, any synthetic acidic amino acid, Lys, Arg,ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any synthetic basic aminoacid, Ala, an aliphatic amino acid bearing linear or branched saturatedhydrocarbon chains such as Leu (D or L), Ile and Val or non-naturalderivatives of the aliphatic amino acid, Ser, Thr, Pro, Hyp, g-Ser,g-Thr, g-Hyp or any synthetic hydroxylated amino acid; Xaa₅ is Lys, Arg,ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any synthetic basic aminoacid, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, an aliphatic amino acid bearinglinear or branched saturated hydrocarbon chains such as Leu (D or L),Ile and Val or non-natural derivatives of the aliphatic amino acid, Glu,Gla, Gln, Asp, Asn, any synthetic acidic amino acid, Pro or Hyp; Xaa₆ isTrp (D or L), neo-Trp, halo-Trp (D or L), Gly, Tyr, meta-Tyr, ortho-Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr, Glu, Gla, Gln, Asp, Asn, any synthetic acidic amino acid;Xaa₇ is Glu, Gla, Gln, Asp, Asn, any synthetic acidic amino acid, Met,norleucine (Nle), Ala, an aliphatic amino acid bearing linear orbranched saturated hydrocarbon chains such as Leu (D or L), Ile and Valor non-natural derivatives of the aliphatic amino acid, Tyr, meta-Tyr,ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr, Lys, Arg, ornithine, homo-Lys, homoarginine,nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or anysynthetic basic amino acid; Xaa₈ is Leu, Phe, Tyr, meta-Tyr, ortho-Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr, Trp (D or L), neo-Trp, halo-Trp (D or L) or any syntheticaromatic amino acid; Xaa₉ is Pro, Hyp, Gly, an aliphatic amino acidbearing linear or branched saturated hydrocarbon chains such as Leu (Dor L), Ile and Val or non-natural derivatives of the aliphatic aminoacid; Xaa₁₀ is Thr, Ser, g-Thr, g-Ser, Ala, an aliphatic amino acidbearing linear or branched saturated hydrocarbon chains such as Leu (Dor L), Ile and Val or non-natural derivatives of the aliphatic aminoacid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Trp (D or L),neo-Trp, halo-Trp (D or L) or any synthetic aromatic amino acid; Xaa₁₁,is Pro, Hyp, Ser, Thr, g-Hyp, g-Ser, g-Thr or any hydroxylated aminoacid; Xaa₁₂ is an aliphatic amino acid bearing linear or branchedsaturated hydrocarbon chains such as Leu (D or L), Ile and Val ornon-natural derivatives of the aliphatic amino acid, Phe, Tyr, meta-Tyr,ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr, Lys, Arg, ornithine, homo-Lys, homoarginine,nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or anysynthetic basic amino acid; Xaa₁₃ is Pro, Hyp, an aliphatic amino acidbearing linear or branched saturated hydrocarbon chains such as Leu (Dor L), Ile and Val or non-natural derivatives of the aliphatic aminoacid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys,N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any syntheticbasic amino acid; Xaa₁₄ is Gly, His, Lys, Arg, ornithine, homo-Lys,homoarginine, nor-Lys, N-methyl-Lys, N,N-dimethyl-Lys,N,N′,N″-trimethyl-Lys or any synthetic basic amino acid; Xaa₁₅ isdes-Xaa₁₅, Ser, Thr, g-Ser, g-Thr, Val, Asn, Phe, Tyr, meta-Tyr,ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr, Trp (D or L), neo-Trp, halo-Trp (D or L) orany synthetic aromatic amino acid;Xaa₁₆ is Met, Nle, an aliphatic aminoacid bearing linear or branched saturated hydrocarbon chains such as Leu(D or L), Ile and Val or non-natural derivatives of the aliphatic aminoacid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Trp (D or L),neo-Trp, halo-Trp (D or L), any synthetic aromatic amino acid, Arg, Lys,ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any synthetic basic aminoacid; Xaa₁₇ is Pro, Hyp, Ser, Thr, g-Hyp, g-Ser, g-Thr, any hydroxylatedamino acid, Ala, Met, Leu, Glu, Gla, Gln, Asp, Asn, any synthetic acidicamino acid, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, His or Gly; Xaa₁₈is Gly, Ala, Ser, Thr, Pro, Hyp, g-Ser, g-Thr, g-Hyp, Glu, Asn or Gln;Xaa₁₉ is Leu, Gly, Asn, Trp (D or L), neo-Trp or halo-Tip (D or L);Xaa₂₀ is des-Xaa₂₀, Leu or Trp (D or L), neo-Trp or halo-Tip (D or L);Xaa₂₁ is des-Xaa₂₁ or an aliphatic amino acid bearing linear or branchedsaturated hydrocarbon chains such as Leu (D or L), Ile and Val ornon-natural derivatives of the aliphatic amino acid; Xaa₂₂ is des-Xaa₂₂,Gly, Met, Nle, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Trp (D or L),neo-Trp, halo-Trp (D or L) or any synthetic aromatic amino acid; Xaa₂₃is des-Xaa₂₃, Pro, Hyp, Ala, an aliphatic amino acid bearing linear orbranched saturated hydrocarbon chains such as Leu (D or L), Ile and Valor non-natural derivatives of the aliphatic amino acid, Phe, Tyr,meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr, Tip (D or L), neo-Trp, halo-Trp (D or L) orany synthetic aromatic amino acid; Xaa₂₄ is Ala, an aliphatic amino acidbearing linear or branched saturated hydrocarbon chains such as Leu (Dor L), Ile and Val or non-natural derivatives of the aliphatic aminoacid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Trp (D or L),neo-Trp, halo-Trp (D or L) or any synthetic aromatic amino acid; Xaa₂₅is Ala, an aliphatic amino acid bearing linear or branched saturatedhydrocarbon chains such as Leu (D or L), Ile and Val or non-naturalderivatives of the aliphatic amino acid, Tyr, meta-Tyr, ortho-Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr or Phe; Xaa₂₆ is an aliphatic amino acid bearing linear orbranched saturated hydrocarbon chains such as Leu (D or L), Ile and Valor non-natural derivatives of the aliphatic amino acid; Xaa₂₇ isdes-Xaa₂₇, Asp, Glu, Gla, Pro, Hyp, Ser, Thr, g-Hyp, g-Ser, g-Ser or anysynthetic hydroxylated amino acid; Xaa₂₈ is des-Xaa₂₈, Glu, Gla, Gln,Asp, Asn, any synthetic acidic amino acid, Lys, Arg, ornithine,homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys,N,N′,N′″-trimethyl-Lys, any synthetic basic amino acid, Ile, Ser, Thr,g-Ser or g-Thr; Xaa₂₉ is des-Xa₉, Pro, Hyp, Tyr, meta-Tyr, ortho-Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr ornitro-Tyr; Xaa₃₀ is des-Xaa₃₀ or Phe.
 3. The method of claim 2, whereinsaid μO-conopeptide is selected from the group consisting of:Ala-Cys-Arg-Gln-Xaa₁-Xaa₂-Xaa₃-Phe-Cys-Leu-Val-Xaa₄-Ile-Ile-Gly-Xaa₂-Ile-Xaa₂-Cys-Cys-Ala-Gly-Leu-Ile-Cys-Gly-Xaa₄-Phe-Val-Cys-Leu(SEQ ID NO:3);Xaa₄-Thr-Cys-Leu-Xaa₁-Gln-Asp-Xaa₁-Phe-Cys-Ile-Ile-Xaa₄-Leu-Ile-Gly-Thr-Leu-Xaa₂-Cys-Cys-Ser-Gly-Leu-Ile-Cys-Gly-Phe-Phe-Val-Cys-Val-Xaa₄-Xaa₁-Xaa₄-Phe(SEQ IDNO:4);Asp-Cys-Xaa₃-Ala-Asp-Gly-Ala-Phe-Cys-Gly-Ile-Xaa₄-Ile-Vla-Xaa₁-Asn-Xaa₅-Met-Cys-Cys-Ser-Asn-Leu-Cys-Ile-Phe-Ala-Cys-Val-Xaa₄-Xaa₃-Xaa₂(SEQ IDNO:5);Asp-Cys-His-Xaa₃-Arg-Xaa₅-Asp-Xaa₅-Cys-Xaa₄-Ala-Ser-Ile-Leu-Gly-Val-Ile-Xaa₂-Cys-Cys-Xaa₃-Gly-Leu-Ile-Cys-Phe-Ile-Ala-Phe-Cys-Ile(SEQ IDNO:6);Asp-Cys-Gln-Xaa₃-Xaa₁-Xaa₅-Xaa₃-Phe-Cys-Ile-Val-Xaa₄-Ile-Leu-Gly-Phe-Val-Xaa₂-Cys-Cys-Xaa₄-Gly-Leu-Ile-Cys-Gly-Xaa₄-Phe-Val-Cys-Val-Asp-Ile(SEQ ID NO:7);Xaa₄-Thr-Cys-Val-Ser-Xaa₂-Asn-Val-Phe-Cys-Gly-Val-Xaa₄-Leu-Val-Gly-Thr-Xaa₂-Leu-Cys-Cys-Ser-Gly-Leu-Val-Cys-Leu-Val-Val-Cys-Ile(SEQ IDNO:8);Cys-Arg-Xaa₄-Arg-Gly-Met-Phe-Cys-Gly-Phe-Xaa₄-Xaa₁-Xaa₄-Gly-Xaa₄-Xaa₂-Cys-Cys-Asn-Gly-Xaa₅-Cys-Phe-Phe-Val-Cys-Ile(SEQ IDNO:9);Arg-Xaa₅-Cys-Ala-Leu-Asp-Gly-Xaa₃-Leu-Cys-Ile-Ile-Xaa₄-Val-Ile-Gly-Ser-Ile-Phe-Cys-Cys-His-Gly-Ile-Cys-Met-Ile-Xaa₂-Cys-Val(SEQ IDNO:10);Asp-Cys-Arg-Xaa₄-Val-Gly-Gln-Xaa₂-Cys-Gly-Ile-Xa₄-Xaa₂-Xaa₁-His-Asn-Xaa₅-Arg-Cys-Cys-Ser-Gln-Leu-Cys-Ala-Ile-Ile-Cys-Val-Ser(SEQ IDNO:11);Gly-Cys-Leu-Asp-Xaa₄-Gly-Xaa₂-Phe-Cys-Gly-Thr-Xaa₄-Phe-Leu-Gly-Ala-Xaa₂-Cys-Cys-Gly-Gly-Ile-Cys-Leu-Ile-Val-Cys-Ile-Xaa₃-Thr(SEQ IDNO:12);Asp-Cys-Xaa₃-Ala-Asp-Gly-Ala-Phe-Cys-Gly-Ile-Xaa₄-Thr-Val-Xaa₁-Asn-Xaa₅-Met-Cys-Cys-Ser-Asn-Leu-Cys-Ile-Phe-Ala-Cys-Val-Xaa₄-Xaa₃-Xaa₂(SEQ IDNO:14);Asp-Cys-Gln-Xaa₃-Xaa₃-Xaa₅-Xaa₃-Phe-Cys-Ile-Val-Xaa₄-Ile-Leu-Gly-Phe-Val-Xaa₂-Cys-Cys-Xaa₄-Gly-Leu-Ile-Cys-Gly-Xaa₄-Phe-Val-Cys-Val(SEQ IDNO:15);Ala-Cys-Arg-Gln-Xaa₁-Xaa₂-Xaa₃-Phe-Cys-Leu-Val-Xaa₄-Ile-Ile-Gly-Xaa₂-Ile-Xaa₂-Cys-Cys-Ala-Gly-Leu-Ile-Cys-Gly-Xaa₄-Phe-Val-Cys-Leu(SEQ ID NO:16);andXaa₄-Thr-Cys-Leu-Xaa₁-Gln-Asp-Xaa₁-Phe-Cys-Ile-Ile-Xaa₄-Leu-Ile-Gly-Thr-Leu-Xaa₂-Cys-Cys-Ser-Gly-Leu-Ile-Cys-Gly-Phe-Phe-Val-Cys-Val-Xaa₄-Xaa₁-Xaa₄-Phe(SEQ ID NO:17), wherein Xaa₁ is Lys, N-methy-Lys, N,N-dimethyl-Lys orN,N,N-trimethyl-Lys; Xaa₂ is Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; Xaa₃ is Glu orgamma-carboxy-Glu (Gla); Xaa₄ is Pro or hydroxy-Pro; Xaa₅ is Trp orhalo-Trp; and the C-terminus contains a carboxyl or amide group.
 4. Themethod of claim 1, wherein the pain is chronic pain or acuteinflammatory pain.
 5. The method of claim 1, wherein the pain isneuropathic pain.
 6. The method of claim 1, wherein the active agent isadministered prior to surgery.
 7. The method of claim 1, wherein theactive agent is administered as a spinal anesthetic.
 8. The method ofclaim 1, wherein the active agent is administered as a local anesthetic.9. The method of claim 8, wherein the active agent is administeredtopically.
 10. The method of claim 9, wherein the pain is pain inepithelial tissue.
 11. The method of claim 10, wherein the pain inepithelial tissue is associated with damage or loss to the epithelialtissue.
 12. The method of claim 9, wherein the pain is in the cornea.13. The method of claim 1, wherein said active agent is administered inan amount from about 1 ng to about 1000 mg per day.
 14. The method ofclaim 1, wherein said active agent is administered in an amount fromabout 100 ng to about 100 mg per day.
 15. The method of claim 1, whereinsaid active agent is administered in an amount from about 1 μg to about10 mg per day.
 16. An isolated nucleic acid comprising a nucleic acidcoding for a μO-conopeptide precursor comprising an amino acid sequenceselected from the group of amino acid sequences set forth in Tables1-11.
 17. The nucleic acid of claim 16 wherein the nucleic acidcomprises a nucleotide sequence selected from the group of nucleotidesequences set forth in Tables 1-11 or their complements.
 18. Asubstantially pure μO-conopeptide precursor comprising an amino acidsequence selected from the group of amino acid sequences set forth inTables 1-11.
 19. A substantially pure μO-conotopeptide having thegeneric formula I:Xaa₁-Xaa₂-Cys-Xaa₃-Xaa₄-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Cys-Xaa₉-Xaa₁₀-Xaa₁₁-Xaa₁₂-Xaa₁₃-Xaa₁₄-Xaa₁₅-Xaa₁₆-Xaa₁₇-Cys-Xaa₁₈-Xaa₁₉-Xaa₂₀-Xaa₂₁-Xaa₂₂-Xaa₂₃-Xaa₂₄-Cys-Xaa₂₅-Xaa₂₆Xaa₂₇-Xaa₂₈-Xaa₂₉-Xaa₃₀(SEQ ID NO:1), wherein Xaa₁ is des-Xaa₁, Pro, hydroxy-Pro (Hyp), Arg,Lys, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any synthetic basic aminoacid; Xaa₂ is des-Xaa₂, Ala, Gly, Asp, Glu, γ-carboxy-glutamate (Gla),any synthetic acidic amino acid, Thr, Ser, g-Thr (where g isglycosylation), g-Ser, Trp (D or L), neo-Trp or halo-Trp (D or L) orXaa₂ may be pyroglutamate if Xaa₁ is des-Xaa₁; Xaa₃ is Arg, Lys,ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any synthetic basic aminoacid, Ser, Thr, g-Ser, g-Thr, Ala, an aliphatic amino acid bearinglinear or branched saturated hydrocarbon chains such as Leu (D or L),Ile and Val or non-natural derivatives of the aliphatic amino acid, His,Glu, Gln, Gla, Asp, Asn or any synthetic acidic amino acid; Xaa₄ is Glu,Gla, Gln, Asp, Asn, any synthetic acidic amino acid, Lys, Arg,ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any synthetic basic amino acid,Ala, an aliphatic amino acid bearing linear or branched saturatedhydrocarbon chains such as Leu (D or L), Ile and Val or non-naturalderivatives of the aliphatic amino acid, Ser, Thr, Pro, Hyp, g-Ser,g-Thr, g-Hyp or any synthetic hydroxylated amino acid; Xaa₅ is Lys, Arg,ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any synthetic basic aminoacid, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, an aliphatic amino acid bearinglinear or branched saturated hydrocarbon chains such as Leu (D or L),Ile and Val or non-natural derivatives of the aliphatic amino acid, Glu,Gla, Gln, Asp, Asn, any synthetic acidic amino acid, Pro or Hyp; Xaa₆ isTrp (D or L), neo-Trp, halo-Trp (D or L), Gly, Tyr, meta-Tyr, ortho-Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr, Glu, Gla, Gln, Asp, Asn, any synthetic acidic amino acid;Xaa₇ is Glu, Gla, Gln, Asp, Asn, any synthetic acidic amino acid, Met,norleucine (Nle), Ala, an aliphatic amino acid bearing linear orbranched saturated hydrocarbon chains such as Leu (D or L), Ile and Valor non-natural derivatives of the aliphatic amino acid, Tyr, meta-Tyr,ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr, Lys, Arg, ornithine, homo-Lys, homoarginine,nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or anysynthetic basic amino acid; Xaa₈ is Leu, Phe, Tyr, meta-Tyr, ortho-Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr, Trp (D or L), neo-Trp, halo-Trp (D or L) or any syntheticaromatic amino acid; Xaa₉ is Pro, Hyp, Gly, an aliphatic amino acidbearing linear or branched saturated hydrocarbon chains such as Leu (Dor L), Ile and Val or non-natural derivatives of the aliphatic aminoacid; Xaa₁₀ is Thr, Ser, g-Thr, g-Ser, Ala, an aliphatic amino acidbearing linear or branched saturated hydrocarbon chains such as Leu (Dor L), Ile and Val or non-natural derivatives of the aliphatic aminoacid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Trp (D or L),neo-Trp, halo-Tip (D or L) or any synthetic aromatic amino acid; Xaa₁₁is Pro, Hyp, Ser, Thr, g-Hyp, g-Ser, g-Thr or any hydroxylated aminoacid; Xaa₁₂ is an aliphatic amino acid bearing linear or branchedsaturated hydrocarbon chains such as Leu i(D or L), Ile and Val ornon-natural derivatives of the aliphatic amino acid, Phe, Tyr, meta-Tyr,ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr, Lys, Arg, ornithine, homo-Lys, homoarginine,nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or anysynthetic basic amino acid; Xaa₁₃ is Pro, Hyp, an aliphatic amino acidbearing linear or branched saturated hydrocarbon chains such as Leu (Dor L), Ile and Val or non-natural derivatives of the aliphatic aminoacid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys,N-methyl-Lys, N,N′-dimethyl-Lys, 14,N′,N″-trimethyl-Lys or any syntheticbasic amino acid; Xaa₁₄ is Gly, His, Lys, Arg, ornithine, homo-Lys,homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys,N,N′,N″-trimethyl-Lys or any synthetic basic amino acid; Xaa₁₅ isdes-Xaa₁₅, Ser, Thr, g-Ser, g-Thr, Val, Asn, Phe, Tyr, meta-Tyr,ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr,O-phospho-Tyr, nitro-Tyr, Trp (D or L), neo-Trp, halo-Trp (D or L) orany synthetic aromatic amino acid;Xaa₁₆ is Met, Nle, an aliphatic aminoacid bearing linear or branched saturated hydrocarbon chains such as Leu(D or L), Ile and Val or non-natural derivatives of the aliphatic aminoacid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Trp (D or L),neo-Trp, halo-Trp (D or L), any synthetic aromatic amino acid, Arg, Lys,ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys,N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any synthetic basic aminoacid; Xaa₁₇ is Pro, Hyp, Ser, Thr, g-Hyp, g-Ser, g-Thr, any hydroxylatedamino acid, Ala, Met, Leu, Glu, Gla, Gln, Asp, Asn, any synthetic acidicamino acid, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, His or Gly; Xaa₁₈is Gly, Ala, Ser, Thr, Pro, Hyp, g-Ser, g-Thr, g-Hyp, Glu, Asn or Gln;Xaa₁₉ is Leu, Gly, Asn, Trp (D or L), neo-Trp or halo-Trp (D or L);Xaa₂₀ is des-Xaa₂₀, Leu or Trp (D or L), neo-Trp) or halo-Trp (D or L);Xaa₂₁ is des-Xaa₂₁ or an aliphatic amino acid bearing linear or branchedsaturated hydrocarbon chains such as Leu (D or L), Ile and Val ornon-natural derivatives of the aliphatic amino acid; Xaa₂₂ is des-Xaa₂₂,Gly, Met, Nle, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Trp (D or L),neo-Trp, halo-Trp (D or L) or any synthetic aromatic amino acid; Xaa₂₃is des-Xaa₂₃, Pro, Hyp, Ala, an aliphatic amino acid bearing linear orbranched saturated hydrocarbon chains such as Leu (D or L), Ile and Valor non-natural derivatives of the aliphatic amino acid, Phe, Tyr,meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho)-Tyr,O-phospho-Tyr, nitro-Tyr, Trp (D or L), neo-Trp, halo-Trp (D or L) orany synthetic aromatic amino acid; Xaa₂₄ is Ala, an aliphatic amino acidbearing linear or branched saturated hydrocarbon chains such as Leu (Dor L), Ile and Val or non-natural derivatives of the aliphatic aminoacid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr,di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Trp (D or L),neo-Trp, halo-Trp (D or L) or any synthetic aromatic amino acid; Xaa₂₅is Ala, an aliphatic amino acid bearing linear or branched saturatedhydrocarbon chains such as Leu (D or L), Ile and Val or non-naturalderivatives of the aliphatic amino acid, Tyr, meta-Tyr, ortho-Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr,nitro-Tyr or Phe; Xaa₁₆ is an aliphatic amino a(id bearing linear orbranched saturated hydrocarbon chains such as Leu (D or L), Ile and Valor non-natural derivatives of the aliphatic amino acid; Xaa₂₇ isdes-Xaa₁₇, Asp, Glu, Gla, Pro, Hyp, Ser, Thr, g-Hyp, g-Ser, g-Ser or anysynthetic hydroxylated amino acid; Xaa₂₈ is des-Xaa₁₈, Glu, Gla, Gln,Asp, Asn, any synthetic acidic amino acid, Lys, Arg, ornithine,homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys,N,N′,N″-trimethyl-Lys, any synthetic basic amino acid, Ile, Ser, Thr,g-Ser or g-Thr; Xaa₂₉ is des-Xaa₂₉, Pro, Hyp, Tyr, meta-Tyr, ortho-Tyr,nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr ornitro-Tyr; Xaa₃₀ is des-Xaa₃₀ or Phe, with the proviso that saidμO-conopeptide is not MrVIA/B.
 20. The substantially pureμO-conotopeptide of claim 19 selected from the group consisting of:Ala-Cys-Arg-Gln-Xaa₁-Xaa₂-Xaa₃-Phe-Cys-Leu-Val-Xaa₄-Ile-Ile-Gly-Xaa₂-Ile-Xaa₂-Cys-Cys-Ala-Gly-Leu-Ile-Cys-Gly-Xaa₄-Phe-Val-Cys-Leu(SEQ IDNO:3);Xaa₄-Thr-Cys-Leu-Xaa₁-Gln-Asp-Xaa₁-Phe-Cys-Ile-Ile-Xaa₄-Leu-Ile-Gly-Thr-Leu-Xaa₂-Cys-Cys-Ser-Gly-Leu-Ile-Cys-Gly-Pho-Phe-Val-Cys-Val-Xaa₄-Xaa₁-Xaa₄-Phe(SEQ IDNO:4);Asp-Cys-Xaa₃-Ala-Asp-Gly-Ala-Phe-Cys-Gly-Ile-Xaa₄-Ile-Vla-Xaa₁-Asn-Xaa₅-Met-Cys-Cys-Ser-Asn-Leu-Cys-Ile-Phe-Ala-Cys-Val-Xaa₄-Xaa₃-Xaa₂(SEQ IDNO:5);Asp-Cys-His-Xaa₃-Arg-Xaa₅-Asp-Xaa₅-Cys-Xaa₄-Ala-Ser-Ile-Leu-Gly-Val-Ile-Xaa₂-Cys-Cys-Xaa₃-Gly-Leu-Ile-Cys-Phe-Ile-Ala-Phe-Cys-Ile(SEQ IDNO:6);Asp-Cys-Gln-Xaa₃-Xaa₁-Xaa₅-Xaa₃-Phe-Cys-Ile-Val-Xaa₄-Ile-Leu-Gly-Phe-Val-Xaa₂-Cys-Cys-Xaa₄-Gly-Leu-Ile-Cys-Gly-Xaa₄-Phe-Val-Cys-Val-Asp-Ile(SEQ IDNO:7);Xaa₄-Thr-Cys-Val-Ser-Xaa₂-Asn-Val-Phe-Cys-Gly-Val-Xaa₄-Leu-Val-Gly-Thr-Xaa₂-Leu-Cys-Cys-Ser-Gly-Leu-Val-Cys-Leu-Val-Val-Cys-Ile(SEQ IDNO:8);Cys-Arg-Xaa₄-Arg-Gly-Met-Phe-Cys-Gly-Phe-Xaa₄-Xaa₁-Xaa₄-Gly-Xaa₄-Xaa₂-Cys-Cys-Asn-Gly-Xaa₅-Cys-Phe-Phe-Val-Cys-Ile(SEQ IDNO:9);Arg-Xaa₅-Cys-Ala-Leu-Asp-Gly-Xaa₃-Leu-Cys-Ile-lle-Xaa₄-Val-Ile-Gly-Ser-Ile-Phe-Cys-Cys-His-Gly-Ile-Cys-Met-Ile-Xaa₂-Cys-Val(SEQ IDNO:10);Asp-Cys-Arg-Xaa₄-Val-Gly-Gln-Xaa₂-Cys-Gly-Ile-Xaa₄-Xaa₂-Xaa₁-His-Asn-Xaa₅-Arg-Cys-Cys-Ser-Gln-Leu-Cys-Ala-Ile-Ile-Cys-Val-Ser(SEQ IDNO:1);Gly-Cys-Leu-Asp-Xaa₄-Gly-Xaa₂-Phe-Cys-Gly-Thr-Xaa₄-Phe-Leu-Gly-Ala-Xaa₂-Cys-Cys-Gly-Gly-Ile-Cys-Leu-Ile-Val-Cys-Ile-Xaa₃-Thr(SEQ IDNO:12);Asp-Cys-Xaa₃-Ala-Asp-Gly-Ala-Phe-Cys-Gly-Ile-Xaa₄-Thr-Val-Xaa₁-Asn-Xaa₅-Met-Cys-Cys-Ser-Asn-Leu-Cys-Ile-Phe-Ala-Cys-Val-Xaa₄-Xaa₃-Xaa₂(SEQ IDNO:14);Asp-Cys-Gln-Xaa₃-Xaa₃-Xaa₅-Xaa₃-Phe-Cys-Ile-Val-Xaa₄-Ile-Leu-Gly-Phe-Val-Xaa₂-Cys-Cys-Xaa₄-Gly-Leu-Ile-Cys-Gly-Xaa₄-Phe-Val-Cys-Val(SEQ IDNO:15);Ala-Cys-Arg-Gln-Xaa₁-Xaa₂-Xaa₃-Phe-Cys-Leu-Val-Xaa₄-Ile-Ile-Gly-Xaa₂-Ile-Xaa₂-Cys-Cys-Ala-Gly-Leu-Ile-Cys-Gly-Xaa₄-Phe-Val-Cys-Leu(SEQ ID NO:16);andXaa₄-Thr-Cys-Leu-Xaa₁-Gln-Asp-Xaa₁-Phe-Cys-Ile-Ile-Xaa₄-Leu-Ile-Gly-Thr-Leu-Xaa₂-Cys-Cys-Ser-Gly-Leu-Ile-Cys-Gly-Phe-Phe-Val-Cys-Val-Xaa₄-Xaa₁-Xaa₄-Phe(SEQ ID NO:17),wherein Xaa₁ is Lys, N-methy-Lys, N,N-dimethyl-Lys orN,N,N-trimethyl-Lys; Xaa₂ is Tyr, mono-halo-Tyr, di-halo-Tyr,O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; Xaa₃ is Glu orgamma-carboxy-Glu (Gla); Xaa₄ is Pro or hydroxy-Pro; Xaa₅ is Trp orhalo-Trp; and the C-terminus contains a carboxyl or amide group.
 21. Apharmaceutical composition comprising the μO-conopeptide of claim 19 ora pharmaceutically acceptable salt or solvate thereof and apharmaceutically acceptable carrier.
 22. A pharmaceutical compositioncomprising the μO-conopeptide of claim 20 or a pharmaceuticallyacceptable salt or solvate thereof and a pharmaceutically acceptablecarrier.